2-aminobenzoxazole derivatives and combinatorial libraries thereof

ABSTRACT

The present invention relates to novel 2-aminobenzoxazole derivative compounds of the following formula:  
                 
 
     wherein R 1  to R 4  and Z have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing 2-aminobenzoxazole derivative compounds.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

[0001] The present invention relates generally to the synthesis ofcompounds comprising heterocyclic rings. In one embodiment, theinvention provides novel 2-aminobenzoxazole derivative compounds as wellas novel combinatorial libraries comprised of such compounds.

BACKGROUND INFORMATION

[0002] The process of discovering new therapeutically active compoundsfor a given indication involves the screening of all compounds fromavailable compound collections. From the compounds tested, one or morestructures is selected as a promising lead. A large number of relatedanalogs are then synthesized in order to develop a structure-activityrelationship and select one or more optimal compounds. With traditional“one-at-a-time” synthesis and biological testing of analogs, thisoptimization process is long and labor intensive. Adding significantnumbers of new structures to the compound collections used in theinitial screening step of the discovery and optimization process cannotbe accomplished with traditional “one-at-a-time” synthesis methods,except over a time frame of years or even decades. Faster methods areneeded that allow for the preparation of up to thousands of relatedcompounds in a matter of days or a few weeks. This need is particularlyevident when synthesizing more complex compounds, such as2-aminobenzoxazole derivatives.

[0003] Benzoxazoles and related derivative compounds have been thesubject of investigation in a number of different biological areas. Forexample, such compounds have been proposed or used as 5-HT₃ antagonists,5-HT₃ agonists or 5-HT₄ (5-hydroxytryptamine, or seortonin) agonists(Monge et al., J. Med. Chem., 37:1320 (1994) and Yasao et al., J. Med.Chem., 41:3015 (1998); as antihistamines (Hong et al., Tetr. Lett.,38:5607 (1997); and as immunological agents (St. Gorgiev et al., Eur. J.Med. Chem., 24:639-41 (1989).

[0004] Benzoxazole derivatives have long been the subject of serialchemical synthesis. See, for example, Iwamatsu et al., U.S. Pat. No.5,631,257; Bowles et al., U.S. Pat. No. 5,206,366; De Nanteuil et al.,6,040,327; Griffin et al., 6,015,827; De Nanteuil et al., 5,972,968;Bradbury et al., U.S. Pat. No. 5,387,592; Poss et al., U.S. Pat. No.5,190,942; Arrowsmith et al., U.S. Pat. No. 5,158,964; Iijima et al.,U.S. Pat. No. 4,948,900; Iijima et al., U.S. Pat. No. 4,897,393; Saitohet al., U.S. Pat. No. 4,728,612; Saitoh et al., 4,690,926; Dawson etal., U.S. Pat. No. 4,416,892; Chu-Moyer et al., J. Org. Chem., 60:5721(1995); Lok et al., J. Org. Chem., 61:3289 (1996); and Kover et al.,Synthesis, 1124 (1994).

[0005] Benzoxazole derivative synthesis has even been extended tocombinatorial chemical methods. Wang et al., Tetr. Lett., 38:6529(1997). However, the libraries to date contain compounds of limiteddiversity and complexity. Indeed, more complex benzoxazole derivatives,especially those amino substituted at the 2-position, have beendifficult to attain.

[0006] A need therefore exists to develop more complex libraries basedon heterocyclic medicinal compounds that would need less time and effortin the synthesis and testing required to bring an organic pharmaceuticalproduct to fruition. In short, improved methods for generatingtherapeutically useful heterocyclic compounds, such as2-aminobenzoxazole derivatives, are desired.

[0007] This invention satisfies this need and provides relatedadvantages as well. The present invention overcomes the knownlimitations of classical serial organic synthesis of 2-aminobenzoxazolederivatives, for example, as well as the shortcomings of combinatorialchemistry related to 2-aminobenzoxazole derivatives. The presentinvention allows for rapid generation of large diverse libraries ofcomplex 2-aminobenzoxazole derivatives as discrete molecules.

[0008] The present invention can utilize a readily available pool ofbuilding blocks that can be incorporated into the various regions of themolecule. Furthermore, the method of making the present invention allowsfor the use of building blocks that contain a wide range of diversefunctionality. Such building blocks can provide combinatorial librariesthat consist of large numbers as well as combinatorial libraries thatare extremely diverse with respect to the functionality contained withinthose libraries. The present invention combines the techniques ofsolid-phase synthesis of 2-aminobenzoxazole derivatives and the generaltechniques of synthesis of combinatorial libraries to prepare highlydiverse new 2-aminobenzoxazole derivative compounds.

SUMMARY OF THE INVENTION

[0009] The present invention relates to novel 2-aminobenzoxazolederivative compounds of the following formula:

[0010] wherein R₁ to R₄ and Z have the meanings provided herein.

[0011] The invention further relates to combinatorial librariescontaining two or more such compounds, as well as methods of preparing2-aminobenzoxazole derivative compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 shows a reaction scheme for the combinatorial synthesis of2-aminobenzoxazole derivative compounds, showing Z of the claimedinvention as Formula A. In step 1, R₁—NH₂ is added in the presence ofNaBH₃CN and DMF/1% HOAc (noting that R₁ of this Figure corresponds toR¹¹ or R¹² of the claimed invention). In step 2,carboxy-2-(methylthio)-1,3-benzoxazole is added in the presence of DICand HOBt. In step 3, a diamine is added in the presence of DMSO at 75°C. (noting that R₃ of the Figure corresponds to R₅ of the claimedinvention, and R of the Figure corresponds to R₆ and R₇ of the claimedinvention. In step 4, R₄CO₂H or R₄SO₂Cl is added (noting that X of theFigure and claimed invention includes carbonyl and sulfonyl, and that R₄of the Figure corresponds to R₈ of the claimed invention.

[0013]FIG. 2 shows a similar reaction scheme as FIG. 1, except showing adifferent resin-attached starting material.

[0014]FIG. 3 shows a reaction scheme for the combinatorial synthesis of2-aminobenzoxazole derivative compounds, showing Z of the claimedinvention as Formula B. The reagents, materials and conditions aresimilar to those of FIG. 1, as described above, except that, in step 3,amino alcohol is added in the presence of N,N-dimethylacetamide andtetramethylguanidine at 73° C. (noting that R₃ of the Figure correspondsto the nitrogen heteroatom and R₅ of Forumla b of the claimed invention,and R₄ of the Figure corresponds to R₈ and R₉ of the claimed invention)

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides compounds and combinatoriallibraries of compounds of the formula:

[0016] where R₁ and R₄, and one of R₂ and R₃, are independently ahydrogen atom, halo, hydroxy, protected hydroxy, cyano, C₁ to C₁₂ alkyl,C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ toC₁₂ substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₁ to C₁₂alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyloxy, C₁ to C₁₂ acyl,C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocyclic ring,substituted heterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂substituted heterocycloalkyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, carboxy, protected carboxy, hydroxymethyl, protectedhydroxymethyl, protected amino, protected (monosubstituted)amino,(disubstituted)amino, C₁ to C₁₀ alkyl protected amino, C₁ to C₁₀ alkylprotected (monosubstituted)amino, C₁ to C₁₀ alkyl(disubstituted)amino,C₁ to C₁₀ substituted alkylamino, C₁ to C₁₀ substituted alkyl protected(monosubstituted)amino, C₁ to C₁₀ substituted alkyl(disubstituted)amino,carboxamide, C₁ to C₁₀ alkylthio, C₁ to C₁₀ substituted alkylthio, C₁ toC₁₀ alkylsulfonyl, C₁ to C₁₀ substituted alkylsulfonyl, C₁ to C₁₀alkylsulfoxide, C₁ to C₁₀ substituted alkylsulfoxide, phenylthio,substituted phenylthio, phenylsulfoxide, substituted phenylsulfoxide,phenylsulfonyl, substituted phenylsulfonyl, (i) the formula—C(O)NR¹¹R¹², (ii) the formula —SR¹¹, (iii) the formula —OR¹¹ or (iv)the formula —C(O)OR , wherein R¹¹ and R¹² are, independently, a hydrogenatom, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl,C₂ to C₁₂ substituted alkenyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂ substitutedheterocycloalkyl, heteroaryl, substituted heteroaryl, heterocycle orsubstituted heterocycle;

[0017] the other of R₂ and R₃ is a hydrogen atom, halo, hydroxy,protected hydroxy, carboxy, thio, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ substitutedalkenyl, C₂ to C₁₂ substituted alkynyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂substituted alkoxy, C₁ to C₁₂ acyloxy, C₁ to C₁₂ acyl, C₃ to C₇cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅to C₇ substituted cycloalkenyl, heterocyclic ring, substitutedheterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂ substitutedheterocycloalkyl, phenyl, substituted phenyl, naphthyl, substitutednaphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, carboxy, protected carboxy, hydroxymethyl, protectedhydroxymethyl, protected amino, protected (monosubstituted)amino,(disubstituted)amino, C₁ to C₁₀ alkyl protected amino, C₁ to C₁₀ alkylprotected (monosubstituted)amino, C₁ to C₁₀ alkyl(disubstituted)amino,C₁ to C₁₀ substituted alkyl protected amino, C₁ to C₁₀ substituted alkylprotected (monosubstituted)amino, C₁ to C₁₀ substitutedalkyl(disubstituted)amino, carboxamide, C₁ to C₁₀ alkylthio, C₁ to C₁₀substituted alkylthio, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substitutedalkylsulfonyl, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ substitutedalkylsulfoxide, phenylthio, substituted phenylthio, phenylsulfoxide,substituted phenylsulfoxide, phenylsulfonyl, substituted phenylsulfonyl,(i) the formula —C(O)NR¹¹R¹², (ii) the formula —SR¹¹, (iii) the formula—OR¹¹, (iv) the formula —C(O)OR¹¹ or (V) the formula S(O)₂NR¹¹R¹²,wherein R¹¹ and R¹² are, independently, a hydrogen atom, C₁ to C₁₂alkyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂substituted alkenyl, phenyl, substituted phenyl, naphthyl, substitutednaphthyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁to C₁₂ heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl,heteroaryl, substituted heteroaryl, heterocycle or substitutedheterocycle;

[0018] Z is the structure A:

[0019] or the structure B:

[0020] or the structure C:

[0021] where, in structure A, Q is the formula ((CH₂)_(n)NH)_(m), wherem is 0 or 1, n is 1 to 6 and the alkylene portion of Q is directlyattached to the depicted nitrogen atom in structure A; and the dottedline between R₆ and R₇ indicates that R₆ and R₇ are optionally directlyattached;

[0022] where, in structure B, the depicted cyclic portion is anunsubstituted or substituted heterocycle that is fully saturated,contains 4 to 7 ring atoms, 1 to 2 nitrogen rings atoms and 0 to 1 otherheteroatoms selected from oxygen and sulfur;

[0023] where, in structure C, K is absent or present and, if present, isa C₁ to C₁₂ alkylene;

[0024] R₅ is C₁ to C₁₀ alkylene, C₂ to C₁₀ alkenylene, C₂ to C₁₀alkynylene, C₁ to C₁₀ substituted alkylene, C₂ to C₁₀ substitutedalkenylene, C₂ to C₁₀ substituted alkynylene, substituted epimino, C₁ toC₅ substituted alkylene epimino, thio, C₁ to C₁₀ alkylene thio, C₁ toC₁₀ substituted alkylene thio, sulfonyl, C₁ to C₁₀ alkylene sulfonyl, C₁to C₁₀ substituted alkylene sulfonyl, sulfinyl, C₁ to C₁₀ alkylenesulfinyl, C₁ to C₁₀ substituted alkylene sulfinyl, oxy, C₁ to C₁₀alkylene oxy, C₁ to C₁₀ substituted alkylene oxy, C₁ to C₁₀ alkylenedioxy, C₁ to C₁₀ substituted alkylene dioxy, C₁ to C₁₀ alkylene trioxyor C₁ to C₁₀ substituted alkylene trioxy;

[0025] X is absent or present and, if present, is carbonyl,thiocarbonyl, thioester, sulfonyl and sulfinyl; and

[0026] where R₆ and R₇ are not directly attached to each other, theyare, independently, a hydrogen atom, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl,C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ substitutedalkenyl, C₂ to C₁₂ substituted alkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substitutedcycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C₇ toC₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, cyclic C₂ toC₇ alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene,hydroxymethyl or protected hydroxymethyl; or

[0027] where R₆ and R₇ are directly attached to each other are, theyare, collectively, C₁ to C₅ alkylene, C₂ to C₅ alkenylene, C₂ to C₅alkynylene, C₁ to C₅ substituted alkylene, C₂ to C₅ substitutedalkenylene, C₂ to C₅ substituted alkynylene, substituted epimino, C₁ toC₅ substituted alkylene epimino, thio, C₁ to C₅ alkylene thio, C₁ to C₅substituted alkylene thio, sulfonyl, C₁ to C₅ alkylene sulfonyl, C₁ toC₅ substituted alkylene sulfonyl, sulfinyl, C₁ to C₅ alkylene sulfinyl,C₁ to C₅ substituted alkylene sulfinyl, oxy, C₁ to C₅ alkylene oxy, C₁to C₅ substituted alkylene oxy, C₁ to C₅ alkylene dioxy, C₁ to C₅substituted alkylene dioxy, C₁ to C₅ alkylene trioxy or C₁ to C₅substituted alkylene trioxy; and

[0028] R₈ and, if present, R₉ are, independently, a hydrogen atom, C₁ toC₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substitutedalkyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₃to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocyclic ring,substituted heterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂substituted heterocycloalkyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, protected hydroxymethyl, protected amino,(monosubstituted) amino, protected (monosubstituted) amino,(disubstituted)amino, C₁ to C₁₀ alkylamino, C₁ to C₁₀ alkyl protectedamino, C₁ to C₁₀ alkyl (monosubstituted)amino, C₁ to C₁₀ alkyl,protected (monosubstituted)amino, C₁ to C₁₀ alkyl(disubstituted)amino,C₁ to C₁₀ substituted alkylamino, C₁ to C₁₀ substituted alkyl protectedamino, C₁ to C₁₀ substituted alkyl (monosubstituted)amino, C₁ to C₁₀substituted alkyl protected (monosubstituted)amino, C₁ to C₁₀substituted alkyl(disubstituted)amino, carboxamide, protectedcarboxamide or (i) the formula —C(O)NR¹¹R¹², (ii) the formula —C(O)R¹¹,(iii) the formula —NR¹¹R¹² or (iv) the formula —C(O)OR¹¹, wherein R¹¹and R¹² are, independently, a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, heteroaryl,substituted heteroaryl, heterocycle, substituted heterocycle, C₁ to C₁₂acyl, C₁ to C₁₂ substituted acyl, phenylsulfonyl, substitutedphenylsulfonyl, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substitutedalkylsulfonyl, C₁ to C₁₂ alkylaminocarbonyl, C₁ to C₁₂ substitutedalkylaminocarbonyl, phenylaminocarbonyl or substitutedphenylaminocarbonyl; or

[0029] R₈ and R₉, together with the adjoining nitrogen depicted instructure B are, collectively, heterocycle or substituted heterocycle.

[0030] In one aspect of the above-described invention, there is theproviso that, if X is carbonyl, R₈ is not alkoxy.

[0031] In another aspect of the above-described invention, there is theproviso that X can only be absent where R₆ and R₇ are not directlyattached to each other.

[0032] The subject invention also provides a salt of the above-describedcompound.

[0033] In another embodiment, the subject invention provides a compoundor combinatorial library where:

[0034] R₁ and R₄ are, independently, a hydrogen atom, halo, C₁ to C₁₂alkyl or C₁ to C₁₂ substituted alkyl.

[0035] In an additional embodiment:

[0036] one of R₂ and R₃ is a hydrogen atom, halo, C₁ to C₁₂ alkyl and C₁to C₁₂ substituted alkyl; and the other of R₂ and R₃ is selected fromthe group consisting of hydrogen atom, halo, hydroxy, carboxy, thio,carboxamide, the formula —C(O)NR¹¹R¹² or the formula S(O)₂NR¹¹R ¹²,wherein R¹¹ and R¹² are, independently, a hydrogen atom, C₁ to C₁₂alkyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂substituted alkenyl, phenyl, substituted phenyl, naphthyl, substitutednaphthyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁to C₁₂ heterocycloalkyl or C₁ to C₁₂ substituted heterocycloalkyl.

[0037] In a further embodiment:

[0038] R₆ and R₇ are not directly attached to each other and are,independently, a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂ substitutedalkyl, C₃ to C₇ cycloalkyl or C₃ to C₇ substituted cycloalkyl.

[0039] In Another Embodiment

[0040] R₈ and, if present, R₉ are, independently, a hydrogen atom, C₁ toC₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substitutedalkyl, C₂ to C₁₂ substituted alkenyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substitutedcycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C₇ toC₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, phenyl,substituted phenyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene or substituted cyclic C₂ toC₇ heteroalkylene.

[0041] In a further embodiment, R₈ and R₉, together with the adjoiningnitrogen depicted in structure B are, collectively, a heterocycle orsubstituted heterocycle.

[0042] Another embodiment of the present invention provides that R₅ isC₁ to C₈ alkylene or C₁ to C₈ substituted alkylene.

[0043] In another aspect of the present invention, R₆ and R₇ aredirectly attached to each other and are, collectively, a C₁ to C₅alkylene or C₁ to C₅ substituted alkylene.

[0044] A further aspect of the invention is where X is absent. Inaddition, X can be carbonyl or sulfonyl.

[0045] In a further embodiment of the present invention:

[0046] R₁ and R₄, and one of R₂ and R₃, are, independently, a hydrogenatom, halo, protected hydroxy, cyano, C₁ to C₁₂ alkyl, C₂ to C₁₂alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₁ to C₁₂ alkoxy, C₁to C₁₂ substituted alkoxy, phenyl, substituted phenyl,(disubstituted)amino, C₁ to C₁₀ alkylthio or C₁ to C₁₀ substitutedalkylthio;

[0047] the other of R₂ and R₃ is a hydrogen atom, halo, hydroxy,carboxy, thio, carboxamide, the formula —C(O)NR¹¹R¹² or the formulaS(O)₂NR¹¹R¹², wherein R¹¹ and R¹² are, independently, a hydrogen atom,C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl, C₂ toC₁₂ substituted alkenyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl or C₁ to C₁₂ substitutedheterocycloalkyl; and

[0048] where R₆ and R₇ are not directly attached to each other, theyare, independently, a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₃ to C₇ cycloalkyl or C₃ to C₇ substitutedcycloalkyl;

[0049] R₈ and, if present, R₉ are, independently, a hydrogen atom, C₁ toC₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substitutedalkyl, C₂ to C₁₂ substituted alkenyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substitutedcycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C₇ toC₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, phenyl,substituted phenyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene or substituted cyclic C₂ toC₇ heteroalkylene; or

[0050] R₈ and R₉, together with the adjoining nitrogen depicted instructure B are, collectively, a heterocycle or substituted heterocycle;and

[0051] R₅ is C₁ to C₈ alkylene or C₁ to C₈ substituted alkylene; and

[0052] where R₆ and R₇ are directly attached to each other, they are,collectively, C₁ to C₅ alkylene or C₁ to C₅ substituted alkylene; and

[0053] X is absent or present and, if present, is carbonyl or sulfonyl.

[0054] In an additional embodiment of the present invention, Z is thestructure A. Further, provided is where the cyclic portion of structureA is 1,4-piperazine or 1,4-homopiperazine. In another embodiment, Z isthe structure B.

[0055] In a further embodiment, R₆ and R₇ are directly attached to eachother. Additionally is provided where R₆ and R₇ are not directlyattached to each other.

[0056] In another embodiment:

[0057] R₁ and R₄ are each hydrogen; and

[0058] one of R₂ and R₃ is hydrogen and the other is the formula—C(O)NR¹¹R¹², wherein one of R¹¹ and R¹² is hydrogen and the other is2-morpholin-4-yl-ethyl, 3-pyrrolidin-1-yl-propyl, allyl, 3-fluorobenzyl,2-piperidin-1-yl-ethyl, 4-morpholino-3-propyl, ethyl-4-butyryl,2-methoxyethyl, benzyl, 4-methylbenzyl, N,N-diethylethylene,N,N-diethyl-1,3-propylene, 3,5-dimethoxybenzyl, 4-fluorophenethyl,4-fluorobenzyl, 2-fluorophenethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-pyridin-2-yl-ethyl, propargyl, 2-pyrrolidin-1-yl-ethyl,2-chlorobenzyl, cyclopropyl, pyridin-3-yl-methyl, 2-thiophenemethyl,3-(methylthio)propyl, cyclohexanemethyl, 2-ethoxyethyl, cyclopentyl,cyclohexyl, 3-chlorobenzyl, 4-methoxyphenethyl, 2-(4-chlorophenyl)ethyl,3-dimethylamino-1-propyl, 3,4-dimethoxybenzyl, 2-bromobenzyl,N-(3-propyl)-N-methylaniline, 2-propionic acid, 2-(3-phenyl)-propionicacid, 2-(4-methyl)-pentanoic acid, (±)-tetrahydrofuryl,3-imidazol-1-yl-propyl, 2-trifluoromethylbenzyl, cycloheptyl,2,4-dichlorophenethyl, 1-(3-propyl)-pyrrolidin-2-one,4-tert-butylcyclohexyl, 2,2,6,6-tetramethyl-piperidin-4-yl,5-diethylamino-2-pentyl, 1,3-dimethylbutyl, 2,4-dimethylbenzyl,thiophene-2-ethyl, 4-methoxyphenyl, 4-piperidino-1-carboxylic acid ethylester, 3-methoxybenzyl, N-1-ethyl-N-1-m-tolyl-2-ethyl,1-benzyl-piperidin-4-yl, 1-methyl-3-phenylpropyl, 2-fluorobenzyl,3-(trifluoromethyl)benzyl, piperonyl, 1-naphthalenemethyl,3,4-dichlorobenzyl, (R)-(−)-1-cyclohexylethyl,(+/−)-1-(1-naphthyl)ethyl, 4-(trifluoromethoxy)benzyl or5-guanidinopentanoic acid-2-yl.

[0059] In a further embodiment:

[0060] Z is the structure A or the structure C, where:

[0061] X is carbonyl and the combination of X—R₈ is benzoyl,methoxyacetyl, tert-butylacetyl, 2,4-difluorobenzoyl,2,4-dimethylbenzoyl, 2-ethylhexanoyl, 2-propylpentanoyl,3-indolepropionyl, N-phenylanthranilyl, trans-2-carboxycyclohexanoyl,cyclohex-3-en-oyl, trans-pent-2-en-oyl, 1-methyl-1-cyclohexanoyl,1-acetylpiperidine-4-carbonyl, cyclopropanecarbonyl,methanesulfonylacetyl, 5-hexynoyl, 3-furoyl, 3,4-difluorophenylacetyl,3-benzoyl-benzoyl, 2-(trifluoromethyl)phenylacetyl,4-(trifluoromethyl)phenylacetyl,2-acetylamino-3-(1H-indol-3-yl)-propionyl, 3-(phenylsulfonyl)propionyl,2-benzyloxyphenylacetyl, benzo(b)thiophene-3-acetyl,3-fluoro-2-methyl-benzoyl, 1-methylcyclopropane-1-carboxyl,(−)-menthoxyacetyl, cyclohexyl-1-acetic acid-1-methylcarbonyl,2-(3-trifluoromethyl-phenylamino)-benzoyl, 2-ketobutyryl,2-ethyl-2-hydroxybutyryl, 5-chlorovaleryl,1-acetyl-pyrrolidine-2-carbonyl, 5-chlorothiophene-2-carboxylyl,2-(2-methoxyethoxy)acetyl, 2-methyl-3-furoyl, 6-heptynoyl or5-methylisoxazole-4-carbonyl; or

[0062] X is sulfonyl and the combination of X—R₈ is2-mesitylenesulfonyl, 2-naphthenesulfonyl, 2-thiophenesulfonyl,4-chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, N-acetylsulfanilyl,2-acetomide-4-methyl-5-thiazolesulfonyl, 4-tert-butylbenzenesulfonyl,8-quinolinesulfonyl, 3-chloro-4-fluorobenzenesulphonyl,4-ethylbenzenesulfonyl, pentamethylbenzenesulfonyl,2,4-dichlorobenzenesulphonyl, 2-chloro-6-methylbenzenesulphonyl,3,4-difluorobenzenesulphonyl, 3,5-dichlorobenzenesulfonyl,3-chlorobenzenesulfonyl, 3-fluorobenzenesulphonyl,4-trifluoromethylbenzenesulphonyl,2-(methoxycarbonyl)thiophene-3-sulfonyl, 1-methylimidazole-4-sulfonyl,3-chloro-4-methylbenzenesulfonyl, 4-isopropylbenzenesulphonyl,3,4-dichlorobenzenesulfonyl, 1-naphthalenesulfonyl,3-nitrobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-nitrobenzenesulfonyl,2,3,5,6-tetramethylbenzenesulfonyl, p-xylene-2-sulfonyl,4-n-propylbenzenesulfonyl, 4-n-amylbenzenesulfonyl,2-chlorobenzenesulfonyl, 5-chlorothiophene-2-sulfonyl,m-toluenesulfonyl, 2-bromobenzenesulfonyl, p-styrenesulfonyl,4-pentylbenzene-1-sulfonyl, 4-n-butylbenzenesulfonyl or2-methylsulfonylbenzenesulfonyl.

[0063] Another embodiment of the present invention provides a singlecompound or combinatorial library where:

[0064] Z is the structure A, where:

[0065] m is 0;

[0066] R₅ is 1,4-butylene, 1,2-ethylene or 1,3-propylene;

[0067] R₆ and R₇ are directly attached and, combined, is 1,2-ethylene;or R₆ and R₇ are not directly attached and are each selected from thegroup consisting of hydrogen and ethyl.

[0068] In an additional embodiment:

[0069] Z is structure A, wherein:

[0070] m is 1;

[0071] n is 3;

[0072] R₅ is 1,2-ethylene; and

[0073] R₆ and R₇ are directly attached and, combined, is 1,2-ethylene.

[0074] In yet another embodiment:

[0075] Z is structure C, wherein:

[0076] K is absent or, if present, is 1,3-propylene.

[0077] The present invention also provides where Z is structure B. In afurther embodiment, the cyclic portion of structure B is pyrrolidine,piperidine or piperazine.

[0078] In another embodiment:

[0079] the cyclic portion of structure B is 1,2-pyrrolidene,1,2-piperidene or 1,4-piperazene, where R₅ is directly connected at the2-position, 2-position and 4-position, respectively, of the cyclicportion; and

[0080] R₅ is methylene or ethylene; and

[0081] R₈ and R₉ are, independently, hydrogen, methyl, ethyl,hydroxyethyl, benzyl, cyclohexyl, isobutyl, propyl, butyl, sec-butyl,hexyl, heptyl, allyl, cyanoethyl, 2-picolyl, cyclohexylmethyl,cyclohexylethane-1,1-diyl, N,N-diethylaminoethyl,N,N-dimethylaminopropyl or neopentyl; or

[0082] R₈ and R₉, together with the adjoining nitrogen atom depicted instructure B are, collectively, pyrrolidin-1-yl, piperidin-1-yl,3-(carboxamide)piperidin-1-yl, 2-(carboxamide)pyrrolidin-1-yl,4-(methyl)piperazin-1-yl, morpholin-4-yl,2-(hydroxymethyl)piperidin-1-yl, 4-(ethylcarboxylate)piperidin-1-yl,4-(phenyl)piperazin-1-yl, 4-(2-pyrimidyl)-piperazin-1-yl,thiomorpholin-4-yl, 4-(benzyl)piperazin-1-yl,3-(ethylcarboxylate)piperidin-1-yl, 4-(hydroxy)piperidin-1-yl,3,5-(dimethyl)piperazin-1-yl, homopiperazin-1-yl,4-(methyl)homopiperazin-1-yl, 2-(methyl)piperidin-1-yl,3,5-(dimethyl)piperidin-1-yl, 3-(N,N-dimethylamino)pyrrolidin-1-yl,3-(amino)pyrrolidin-1-yl, homopiperidin-1-yl, decahydroquinolin-1-yl ortertrahydroisoquinolin-1-yl.

[0083] The invention also provides methods of preparing2-aminobenzoxazole derivative compounds and combinatorial libraries. Inone method, such compounds and libraries can be prepared by startingwith, for example, an aldehyde (SASRIN) resin, which can be reacted witha primary amine to form a disubstituted amine attached to resin. SeeStep 1 of FIG. 1 and Step 1 of FIG. 3.

[0084] Alternatively, other resins, such as an mBHA Linker resin, can beused. See FIG. 2.

[0085] Resin-bound 2-aminobenzoxazole derivative compounds can becleaved by treating them, for example, with a solution oftrifluoroacetic acid in dichloromethane (TFA/DCM). With derivativesattached to mBHA Linker resin, cleavage can be achieved usinghydrofluoric acid (HF) gas. The compounds can be extracted from thespent resin, for example, with acetic acid (AcOH).

[0086] A resin-attached amine can be acylated with a benzoxazolederivative that is carboxy-substituted on the benzyl portion of thebicyclic ring. The carboxy substitution can be, for example, at the 5-or 6-position. See Step 2 of FIG. 2 and Step 2 of FIG. 3. However, itshould be understood that the substitution can occur, for example, atthe 4- or 7-position.

[0087] It should also be understood that the benzyl portion of thebenzoxazole may be substituted by a variety of other moieties, such as asulfonyl, which would result in a sulfonamide at that position of thefinal product. Alternatively, a resin-bound hydroxy can react with thecarboxy group of the benzoxazole, resulting in a carboxy moiety at thatposition of the final product. In addition, a resin-bound halide canreact with a phenol (OH) group attached to the 4- to 7-position (i.e.,R₁ to R₄) of the benzoxazole ring, resulting in a hydroxy group at thatposition of the final product. Similarly, a resin-bound halide can reactwith an —SH group attached to the 4- to 7-position (i.e., R₁ to R₄) ofthe benzoxazole ring, resulting in an —SH group at that position of thefinal product.

[0088] Moreover, a resin-bound halide can react with an —OH groupattached to the 4- to 7-position (i.e., R₁ to R₄) of the benzoxazolering, resulting in an —OH group at that position of the final product.The resin can then be cleaved. The resulting product can then react withan alkyl halide or substituted alkyl halide in solution, resulting in an—OR at that position.

[0089] It should also be understood that the benzoxazole derivativeintroduced in this step may be further substituted at any or all of theother positions of the benzene ring (R₁ to R₄ of the claimed invention).For example, a variety of substituted 1,2-aminophenols are commerciallyavailable in the Available Chemicals Directory, many with functionalgroups capable of attachment to resin. In such cases, the benzoxazolering could be formed first in solution.

[0090] The benzoxazole derivative can be further substituted with aleaving group, such as methylthio, at, for example, the 2-position orother positions on the benzyl ring. Other possible leaving groupsinclude chloro and bromo.

[0091] The leaving group can be displaced with a diamine derivative oran amino alcohol derivative. Such a moiety can be, for example, formulaA:

[0092] (excluding “—X—R₈” of formula A);

[0093] or formula B:

[0094] (excluding “—NR₈R₉” of formula B and first having a hydroxyattached to R₅ (i.e., —R₅—OH));

[0095] or formula C:

[0096] (excluding “—X—R₈” of formula C). See Step 3 of FIG. 1, whereFormula A (where Q is absent) is attached; and Step 3 of FIG. 3, whereFormula B (where R₅ is methylene) is attached.

[0097] As discussed above, in formula A, Q is the formula((CH₂)_(n)NH)_(m), where m is 0 or 1, n is 1 to 6 and the alkyleneportion of Q is directly attached to the depicted nitrogen atom informula A; and the dotted line between R₆ and R₇, which are variablegroups, indicates that R₆ and R₇ are optionally directly attached.

[0098] In formula B, the depicted cyclic portion is an unsubstituted orsubstituted heterocycle that is fully saturated, contains 4 to 7 ringatoms, 1 to 2 nitrogen rings atoms and 0 to 1 other heteroatoms selectedfrom oxygen and sulfur, and R₅, R₈ and R₉ are variable groups.

[0099] In formula C, K is absent or present and, if present, is a C₁ toC₁₂ alkylene, X is optionally present as a carbonyl, thiocarbonyl,thioester, sulfonyl or sulfinyl group, and R₈ is a variable group.

[0100] Preferentially, diamines are symmetrical to avoid generation ofregioisomeric mixtures. However, assymetrical diamines may be used, forexample, 1,2-diaminopropane, lysine or 2,3-diaminoproppionic acid.Diamines can have either primary or secondary amine termini.

[0101] The present invention further provides attachment of —Q—X—R₈ offormula A or —X—R₈ of formula C to the rest of the formula by, forexample acylation. Alternatively, attachment of —Q—X—R₈ of formula A or—X—R₈ of formula C to the rest of the formula can be accomplished bysulfonation. See Step 4 of FIG. 1. It should also be understood thatthis attachment can be done via other mechanisms, such as sulfinationand thioacylation.

[0102] The method of the present invention also provides where thedisubstituted amino (—NR₈R₉) portion of formula B is attached to therest of the formula by displacing a leaving group. Such a leaving groupcan be, for example, a halo and, more specifically, bromo. See Steps 4and 5 of FIG. 3.

[0103] When the above-described compounds include one or more chiralcenters, the stereochemistry of such chiral centers can independently bein the R or S configuration, or a mixture of the two. The chiral centerscan be further designated as R or S or R,S or d,D, l,L or d,l, D,L.

[0104] Regarding the compounds and combinatorial libraries describedherein, the suffix “ene” added to any of the described terms means thattwo parts of the substituent are each connected to two other parts inthe compound (unless the substituent contains only one carbon, in whichcase such carbon is connected to two other parts in the compound, forexample, methylene).

[0105] The term “C₁ to C₁₂ alkyl” denotes such radicals as methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyland the like. Preferred “C₁ to C₁₂ alkyl” groups are methyl, ethyl,iso-butyl, sec-butyl and iso-propyl. Similarly, the term “C₁ to C₁₂alkylene” denotes radicals of 1 to 12 carbons connected to two otherparts in the compound.

[0106] The term “C₂ to C₁₂ alkenyl” denotes such radicals as vinyl,allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 5-heptenyl, 6-heptenyl, (as well as octenyl, nonenyl,decenyl, undecenyl, dodecenyl radicals attached at any appropriatecarbon position and the like) as well as dienes and trienes of straightand branched chains.

[0107] The term “C₂ to C₁₂ alkynyl” denotes such radicals as ethanol,propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl (as well asoctynyl, nonynyl, decynyl, undecynyl, dodecynyl radicals attached at anyappropriate carbon position and the like) as well as di- and tri-ynes ofstraight and branched chains.

[0108] The terms “C₁ to C₁₂ substituted alkyl,” “C₂ to C₁₂ substitutedalkenyl,” “C₂ to C₁₂ substituted alkynyl,” “C₁ to C₁₂ substitutedalkylene,” “C₂ to C₁₂ substituted alkenylene” and “C₂ to C₁₂ substitutedalkynylene” denote groups are substituted by one or more, and preferablyone or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C₃to C₇ cycloalkyl, phenyl, naphthyl, amino, protected amino,(monosubstituted)amino, protected (monosubstituted) amino,(disubstituted) amino, guanidino, protected guanidino, heterocyclicring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl,C₁ to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, nitro, carboxy,protected carboxy, carbamoyl, carboxamide, protected carboxamide, N-(C₁to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide,N,N-di(C₁ to C₁₂ alkyl)carboxamide, cyano, methylsulfonylamino, thiol,C₁ to C₁₀ alkylthio or C₁ to C₁₀ alkylsulfonyl groups. The substitutedalkyl groups may be substituted once or more, and preferably once ortwice, with the same or with different substituents.

[0109] Examples of the above substituted alkyl groups include the2-oxo-prop-1-yl, 3-oxo-but-1-yl, cyanomethyl, nitromethyl, chloromethyl,hydroxymethyl, tetrahydropyranyloxymethyl, trityloxymethyl,propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl,allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl,t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl,trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-aminopropyl,1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-chloroethyl,1-fluoroethyl, 2-fluoroethyl, 1-iodoethyl, 2-iodoethyl, 1-chloropropyl,2-chloropropyl, 3-chloropropyl, 1-bromopropyl, 2-bromopropyl,3-bromopropyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl,1-iodopropyl, 2-iodopropyl, 3-iodopropyl, 2-aminoethyl, 1-aminoethyl,N-benzoyl-2-aminoethyl, N-acetyl-2-aminoethyl, N-benzoyl-1-aminoethyl,N-acetyl-1-aminoethyl and the like.

[0110] Examples of the above substituted alkenyl groups includestyrenyl, 3-chloro-propen-1-yl, 3-chloro-buten-1-yl,3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl, 1-cyano-buten-3-yl and thelike. The geometrical isomerism is not critical, and all geometricalisomers for a given substituted alkenyl can be used.

[0111] Examples of the above substituted alkynyl groups includephenylacetylen-1-yl, 1-phenyl-2-propyn-1-yl and the like.

[0112] The term “oxo” denotes a carbon atom bonded to two additionalcarbon atoms substituted with an oxygen atom doubly bonded to the carbonatom, thereby forming a ketone moiety.

[0113] The term “protected oxo” denotes a carbon atom bonded to twoadditional carbon atoms substituted with two alkoxy groups or twicebonded to a substituted diol moiety, thereby forming an acyclic orcyclic ketal moiety.

[0114] The term “C₁ to C₁₂ alkoxy” as used herein denotes groups such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and likegroups. A preferred alkoxy is methoxy. The term “C₁ to C₁₂ substitutedalkoxy” means the alkyl portion of the alkoxy can be substituted in thesame manner as in relation to C₁ to C₁₂ substituted alkyl. Similarly,the term “C₁ to C₁₂ phenylalkoxy” as used herein means “C₁ to C₁₂alkoxy” bonded to a phenyl radical.

[0115] The term “C₁ to C₁₂ acyloxy” denotes herein groups such asformyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy,hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy, decanoyloxy,undecanoyloxy, dodecanoyloxy and the like.

[0116] Similarly, the term “C₁ to C₁₂ acyl” encompasses groups such asformyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl,heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyland the like. Preferred acyl groups are acetyl and benzoyl.

[0117] The term “C₁ to C₁₂ substituted acyl” denotes the acyl groupsubstituted by one or more, and preferably one or two, halogen, hydroxy,protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino,protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclicring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl,C₁ to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, nitro, C₁ to C₁₂alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide,protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁to C₁₂ alkyl)carboxamide, N,N-di(C₁ to C₁₂ alkyl)carboxamide, cyano,methylsulfonylamino, thiol, C₁ to C₁₀ alkylthio or C₁ to C₁₀alkylsulfonyl groups. The substituted acyl groups may be substitutedonce or more, and preferably once or twice, with the same or withdifferent substituents.

[0118] Examples of C₁ to C₁₂ substituted acyl groups include4-phenylbutyroyl, 3-phenylbutyroyl, 3-phenylpropanoyl,2cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and3-dimethylaminobenzoyl.

[0119] The substituent term “C₃ to C₇ cycloalkyl” includes thecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.Similarly, a substituent that can be “C₃ to C₇ cycloalkyl” can also be“C₅ to C₇ cycloalkyl,” which includes the cyclopentyl, cyclohexyl orcycloheptyl rings.

[0120] The substituent term “C₃ to C₇ substituted cycloalkyl” or “C₅ toC₇ substituted cycloalkyl” indicates the above cycloalkyl ringssubstituted by one or two halogen, hydroxy, protected hydroxy, C₁ to C₁₀alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀substituted alkylthio, C₁ to C₁₀ substituted alkylsulfoxide, C₁ to C₁₀substituted alkylsulfonyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂substituted alkyl, C₁ to C₁₂ alkoxy, oxo, protected oxo,(monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy,protected carboxy, phenyl, substituted phenyl, phenylthio,phenylsulfoxide, phenylsulfonyl, amino, or protected amino groups.

[0121] The term “cycloalkylene” means a cycloalkyl, as defined above,where the cycloalkyl radical is bonded at two positions connectingtogether two separate additional groups. Similarly, the term“substituted cycloalkylene” means a cycloalkylene where the cycloalkylradical is bonded at two positions connecting together two separateadditional groups and further bearing at least one additionalsubstituent.

[0122] The term “C₅ to C₇ cycloalkenyl” indicates a 1,2, or3-cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or5-cycloheptenyl ring, while the term “substituted C₅ to C₇ cycloalkenyl”denotes the above C₅ to C₇ cycloalkenyl rings substituted by a C₁ to C₁₂alkyl radical, halogen, hydroxy, protected hydroxy, C₁ to C₁₂ alkoxy,trifluoromethyl, carboxy, protected carboxy, oxo, protected oxo,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, phenyl, substituted phenyl, amino, or protectedamino.

[0123] The term “C₅ to C₇ cycloalkenylene” is a cycloalkenyl ring, asdefined above, where the cycloalkenyl radical is bonded at two positionsconnecting together two separate additional groups. Examples of C₅ to C₇cycloalkenylenes include 1,3-cyclopentylene and 1,2-cyclohexylene.

[0124] Similarly, the term “substituted C₅ to C₇ cycloalkenylene” meansa cycloalkenylene further substituted by halogen, hydroxy, protectedhydroxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀alkylsulfonyl, C₁ to C₁₀ substituted alkylthio, C₁ to C₁₀ substitutedalkylsulfoxide, C₁ to C₁₀ substituted alkylsulfonyl, C₁ to C₁₂ alkyl, C₁to C₁₂ alkoxy, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, oxo,protected oxo, (monosubstituted)amino, (disubstituted)amino,trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl,phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected aminogroup. Examples of substituted C₅ to C₇ cycloalkenylenes include4-chloro-1,3-cyclopentylene and 4-methyl-1,2-cyclohexylene.

[0125] The term “heterocycle” or “heterocyclic ring” denotes optionallysubstituted five-membered to eight-membered rings that have 1 to 4heteroatoms, such as oxygen, sulfur and/or nitrogen, in particularnitrogen, either alone or in conjunction with sulfur or oxygen ringatoms. These five-membered to eight-membered rings may be saturated,fully unsaturated or partially unsaturated, with fully saturated ringsbeing preferred. Preferred heterocyclic rings include morpholino,piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo,tetrahydrothiophen-yl, hexylmethyleneimino and heptylmethyleneimino.

[0126] The term “substituted heterocycle” or “substituted heterocyclicring” means the above-described heterocyclic ring is substituted with,for example, one or more, and preferably one or two, substituents whichare the same or different which substituents can be halogen, hydroxy,protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, carboxy,protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted)amino, protected (monosubstituted) amino,(disubstituted) amino carboxamide, protected carboxamide, N-(C₁ to C₁₂alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-di(C₁to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₁₂alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, heterocycle orsubstituted heterocycle groups.

[0127] The term “heteroaryl” means a heterocyclic aromatic derivativewhich is a five-membered or six-membered ring system having from 1 to 4heteroatoms, such as oxygen, sulfur and/or nitrogen, in particularnitrogen, either alone or in conjunction with sulfur or oxygen ringatoms. Examples of heteroaryls include pyridinyl, pyrimidinyl, andpyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo,phthalimido, thiazolo and the like.

[0128] The term “substituted heteroaryl” means the above-describedheteroaryl is substituted with, for example, one or more, and preferablyone or two, substituents which are the same or different whichsubstituents can be halogen, hydroxy, protected hydroxy, cyano, nitro,C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ toC₁₂ acyl, C₁ to C₁₂ substituted acyl, C₁ to C₁₂ acyloxy, carboxy,protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted) amino, protected (monosubstituted) amino,(disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-di(C₁to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₁₂alkyl)sulfonyl)amino or N-(phenylsulfonyl)amino groups.

[0129] The term “C₇ to C₁₈ phenylalkyl” denotes a C₁ to C₁₂ alkyl groupsubstituted at any position within the alkyl chain by a phenyl. Thedefinition includes groups of the formula: -phenyl-alkyl, -alkyl-phenyland -alkyl-phenyl-alkyl. Examples of such a group include benzyl,2-phenylethyl, 3-phenyl(n-propyl), 4-phenylhexyl, 3-phenyl(n-amyl),3-phenyl(sec-butyl) and the like. Preferred C₇ to C₁₈ phenylalkyl groupsare any one of the preferred alkyl groups described herein combined witha phenyl group.

[0130] Similarly, the term “C₁ to C₁₂ heterocycloalkyl” denotes a C₁ toC₁₂ alkyl group substituted at any position within the alkyl chain by a“heterocycle,” as defined herein. The definition includes groups of theformula: -heterocyclic-alkyl, -alkyl-heterocyclic and-alkyl-heterocyclic-alkyl. Examples of such a group include2-pyridylethyl, 3-piperydyl(n-propyl), 4-furylhexyl,3-piperazyl(n-amyl), 3-morpholyl(sec-butyl) and the like. Preferred C₁to C₁₂ heterocycloalkyl groups are any one of the preferred alkyl groupsdescribed herein combined with any one of the preferred heterocyclegroups described herein.

[0131] The terms “C₇ to C₁₈ substituted phenylalkyl” and “C₁ to C₁₂substituted heterocycloalkyl” denote a C₇ to C₁₈ phenylalkyl group or C₁to C₁₂ heterocycloalkyl substituted (on the alkyl or, where applicable,phenyl or heterocyclic portion) with one or more, and preferably one ortwo, groups chosen from halogen, hydroxy, protected hydroxy, oxo,protected oxo, amino, protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, guanidino, protectedguanidino, heterocyclic ring, substituted heterocyclic ring, C₁ to C₁₂alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂substituted alkoxy, C₃ to C₁₂ acyl, C₁ to C₁₂ substituted acyl, C₁ toC₁₂ acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide,protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁to C₁₂ alkyl)carboxamide, N, N-(C₁ to C₁₂ dialkyl)carboxamide, cyano,N-(C₁ to C₁₂ alkylsulfonyl)amino, thiol, C₁ to C₁₀ alkylthio, C₁ to C₁₀alkylsulfonyl groups; and/or the phenyl group may be substituted withone or more, and preferably one or two, substituents chosen fromhalogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁to C₁₂ substituted alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substitutedalkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ substituted acyl, C₁ to C₁₂ acyloxy,carboxy, protected carboxy, carboxymethyl, protected carboxymethyl,hydroxymethyl, protected hydroxymethyl, amino, protected amino,(monosubstituted) amino, protected (monosubstituted) amino,(disubstituted)amino, carboxamide, protected carboxamide, N-(C₁ to C₁₂alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N, N-di(C₁to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₁₂alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, cyclic C₂ to C₁₂ alkyleneor a phenyl group, substituted or unsubstituted, for a resultingbiphenyl group. The substituted alkyl, phenyl or heterocyclic groups maybe substituted with one or more, and preferably one or two, substituentswhich can be the same or different.

[0132] Examples of the term “C₇ to C₁₈ substituted phenylalkyl” includegroups such as 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl,4-(2,6-dihydroxy phenyl)n-hexyl, 2-(5-cyano-3-methoxyphenyl)n-pentyl,3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl,6-(4-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4aminomethylphenyl)-3-(aminomethyl)n-pentyl, 5-phenyl-3-oxo-n-pent-1-yland the like.

[0133] The term “C₇ to C₁₈ phenylalkylene” specifies a C₇ to C₁₈phenylalkyl, as defined above, where the phenylalkyl radical is bondedat two different positions connecting together two separate additionalgroups. The definition includes groups of the formula: -phenyl-alkyl-,-alkyl-phenyl- and -alkyl-phenyl-alkyl-. Substitutions on the phenylring can be 1,2, 1,3 or 1,4. C₇ to C₁₈ phenylalkylenes include, forexample, 1,4-tolylene and 1,3-xylylene.

[0134] Similarly, the term “C₁ to C₁₂ heterocycloalkylene” specifies aC₁ to C₁₂ heterocycloalkyl, as defined above, where the heterocycloalkylradical is bonded at two different positions connecting together twoseparate additional groups. The definition includes groups of theformula: -heterocyclic-alkyl-, -alkyl-heterocyclic and-alkyl-heterocyclic-alkyl-.

[0135] The terms “C₇ to C₁₈ substituted phenylalkylene” and “C₁ to C₁₂substituted heterocycloalkylene” means a C₇ to C₁₈ phenylalkylene or C₁to C₁₂ heterocycloalkylene as defined above that is further substitutedby halogen, hydroxy, protected hydroxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substitutedalkylthio, C₁ to C₁₀ substituted alkylsulfoxide, C₁ to C₁₀ substitutedalkylsulfonyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substitutedalkyl, C₁ to C₁₂ alkoxy, oxo, protected oxo, (monosubstituted)amino,(disubstituted)amino, trifluoromethyl, carboxy, protected carboxy,phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl,amino, or protected amino group on the phenyl ring or on the alkylgroup.

[0136] The term “substituted phenyl” specifies a phenyl groupsubstituted with one or more, and preferably one or two, moieties chosenfrom the groups consisting of halogen, hydroxy, protected hydroxy,cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂substituted acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy,carboxymethyl, protected carboxymethyl, hydroxymethyl, protectedhydroxymethyl, amino, protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, carboxamide, protectedcarboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂alkyl)carboxamide, N, N-di(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl,N-((C₁ to C₁₂ alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or phenyl,wherein the phenyl is substituted or unsubstituted, such that, forexample, a biphenyl results.

[0137] Examples of the term “substituted phenyl” includes a mono- ordi(halo)phenyl group such as 2,3 or 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3 or 4-bromophenyl,3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2,3 or 4-fluorophenyl andthe like; a mono or di(hydroxy)phenyl group such as 2,3 or4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivativesthereof and the like; a nitrophenyl group such as 2,3 or 4-nitrophenyl;a cyanophenyl group, for example, 2,3 or 4-cyanophenyl; a mono- ordi(alkyl)phenyl group such as 2,3 or 4-methylphenyl, 2,4-dimethylphenyl,2,3 or 4-(iso-propyl)phenyl, 2,3 or 4-ethylphenyl, 2,3 or4-(n-propyl)phenyl and the like; a mono or di(alkoxyl)phenyl group, forexample, 2,6-dimethoxyphenyl, 2,3 or 4-methoxyphenyl, 2,3 or4-ethoxyphenyl, 2,3 or 4-(isopropoxy)phenyl, 2,3 or 4-(t-butoxy)phenyl,3-ethoxy-4-methoxyphenyl and the like; 2,3 or 4-trifluoromethylphenyl; amono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 2,3or 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono-ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 2,3,or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2,3 or 4-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or amono- or di(N-(methylsulfonylamino))phenyl such as 2,3 or4-(N-(methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups wherein the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy4-chlorophenyl and the like.

[0138] The term “phenoxy” denotes a phenyl bonded to an oxygen atom,wherein the binding to the rest of the molecule is through the oxygenatom. The term “substituted phenoxy” specifies a phenoxy groupsubstituted with one or more, and preferably one or two, moieties chosenfrom the groups consisting of halogen, hydroxy, protected hydroxy,cyano, nitro, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substitutedalkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy,carboxymethyl, protected carboxymethyl, hydroxymethyl, protectedhydroxymethyl, amino, protected amino, (monosubstituted)amino, protected(monosubstituted)amino, (disubstituted)amino, carboxamide, protectedcarboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂alkyl)carboxamide, N, N-di(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl,N-((C₁ to C₁₂ alkyl)sulfonyl)amino and N-(phenylsulfonyl)amino.

[0139] Examples of substituted phenoxy include 2-methylphenoxy,2-ethylphenoxy, 2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy,2-tert-butylphenoxy, 2-allylphenoxy, 2-propenylphenoxy,2-cyclopentylphenoxy, 2-fluorophenoxy, 2-(trifluoromethyl)phenoxy,2-chlorophenoxy, 2-bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy,2-isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy,3-isopropylphenoxy, 3-tert-butylphenoxy, 3-pentadecylphenoxy,3-(trifluoromethyl)phenoxy, 3-fluorophenoxy, 3-chlorophenoxy,3-bromophenoxy, 3-iodophenoxy, 3-methoxyphenoxy,3-(trifluoromethoxy)phenoxy, 4-methylphenoxy, 4-ethylphenoxy,4-propylphenoxy, 4-isopropylphenoxy, 4-sec-butylphenoxy,4-tert-butylphenoxy, 4-tert-amylphenoxy, 4-nonylphenoxy,4-dodecylphenoxy, 4-cyclopenylphenoxy, 4-(trifluoromethyl)phenoxy,4-fluorophenoxy, 4-chlorophenoxy, 4-bromophenoxy, 4-iodophenoxy,4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-ethoxyphenoxy,4-propoxyphenoxy, 4-butoxyphenoxy, 4-hexyloxyphenoxy,4-heptyloxyphenoxy, 2,3-dimethylphenoxy, 5,6,7,8-tetrahydro-1-naphthoxy,2,3-dichlorophenoxy, 2,3-dihydro-2,2-dimethyl-7-benzofuranoxy,2,3-dimethoxyphenoxy, 2,6-dimethylphenoxy, 2,6-diisopropylphenoxy,2,6-di-sec-butylphenoxy, 2-tert-butyl-6-methylphenoxy,2,6-di-tert-butylphenoxy, 2-allyl-6-methylphenoxy, 2,6-difluorophenoxy,2,3-difluorophenoxy, 2,6-dichlorophenoxy, 2,6-dibromophenoxy,2-fluoro-6-methoxyphenoxy, 2,6-dimethoxyphenoxy, 3,5-dimethylphenoxy,5-isopropyl-3-methylphenoxy, 3,5-di-tert-butylphenoxy,3,5-bis(trifluoromethyl)phenoxy, 3,5-difluorophenoxy,3,5-dichlorophenoxy, 3,5-dimethoxyphenoxy, 3-chloro-5-methoxyphenoxy,3,4-dimethylphenoxy, 5-indanoxy, 5,6,7,8-tetrahydro-2-naphthoxy,4-chloro-3-methylphenoxy, 2,4-dimethylphenoxy, 2,5-dimethylphenoxy,2-isopropyl-5-methylphenoxy, 4-isopropyl-3-methylphenoxy,5-isopropyl-2-methylphenoxy, 2-tert-butyl-5 -methylphenoxy,2-tert-butyl-4-methylphenoxy, 2,4-di-tert-butylphenoxy,2,4-di-tert-amylphenoxy, 4-fluoro-2-methylphenoxy,4-fluoro-3-methylphenoxy, 2-chloro-4-methylphenoxy,2-chloro-5-methylphenoxy, 4-chloro-2-methylphenoxy,4-chloro-3-ethylphenoxy, 2-bromo-4-methylphenoxy,4-iodo-2-methylphenoxy, 2-chloro-5-(trifluoromethyl)phenoxy,2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,4-difluorophenoxy,4-chloro-2-fluorophenoxy, 3-chloro-4-fluorophenoxy,4-chloro-3-fluorophenoxy, 2-bromo-4-fluorophenoxy,4-bromo-2-fluorophenoxy, 2-bromo-5-fluorophenoxy, 2,4-dichlorophenoxy,3,4-dichlorophenoxy, 2,5-dichlorophenoxy, 2-bromo-4-chlorophenoxy,2-chloro-4-fluorophenoxy, 4-bromo-2-chlorophenoxy, 2,4-dibromophenoxy,2-methoxy-4-methylphenoxy, 4-allyl-2-methylphenoxy,trans-2-ethoxy-5-(1-propenyl)phenoxy, 2-methoxy-4-propenylphenoxy,3,4-dimethoxyphenoxy, 3-ethoxy-4-methoxyphenoxy,4-allyl-2,6-dimethoxyphenoxy, 3,4-methylenedioxyphenoxy,2,3,6-trimethylphenoxy, 2,4-dichloro-3-methylphenoxy,2,3,4-trifluorophenoxy, 2,3,6-trifluorophenoxy, 2,3,5-trifluorophenoxy,2,3,4-trichlorophenoxy, 2,3,6-trichlorophenoxy, 2,3,5-trimethylphenoxy,3,4,5-trimethylphenoxy, 4-chloro-3,5-dimethylphenoxy,4-bromo-3,5-dimethylphenoxy, 2,4,6-trimethylphenoxy,2,6-bis(hydroxymethyl)-4-methylphenoxy,2,6-di-tert-butyl-4-methylphenoxy, 2,6-di-tert-butyl-4-methoxyphenoxy,2,4,5- trifluorophenoxy, 2-chloro-3,5-difluorophenoxy,2,4,6-trichlorophenoxy, 3,4,5-trimethoxyphenoxy, 2,3,5-trichlorophenoxy,4-bromo-2,6-dimethylphenoxy, 4-bromo-6-chloro-2-methylphenoxy,2,6-dibromo-4-methylphenoxy, 2,6-dichloro-4-fluorophenoxy,2,6-dibromo-4-fluorophenoxy, 2,4,6-tribromophenoxy,2,4,6-triiodophenoxy, 2-chloro-4,5-dimethylphenoxy,4-chloro-2-isopropyl-5-methylphenoxy, 2-bromo-4,5-difluorophenoxy,2,4,5-trichlorophenoxy, 2,3,5,6-tetrafluorophenoxy and the like.

[0140] The term “C₇ to C₁₈ substituted phenylalkoxy” denotes a C₇ to C₁₈phenylalkoxy group bonded to the rest of the molecule through the oxygenatom, wherein the phenylalkyl portion is substituted with one or more,and preferably one or two, groups selected from halogen, hydroxy,protected hydroxy, oxo, protected oxo, amino, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, guanidino, heterocyclic ring, substitutedheterocyclic ring, C₁ to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy,nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protectedcarboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂alkyl)carboxamide, N, N-(C₁ to C₁₂ dialkyl)carboxamide, cyano, N-(C₁ toC₁₂ alkylsulfonyl)amino, thiol, C₁ to C₁₀ alkylthio, C₁ to C₁₀alkylsulfonyl groups; and/or the phenyl group can be substituted withone or more, and preferably one or two, substituents chosen fromhalogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₁₂ alkyl, C₁to C₁₂ alkoxy, C₁ to C₁₂ acyl, C₁ to C₁₂ acyloxy, carboxy, protectedcarboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl,protected hydroxymethyl, amino, protected amino, (monosubstituted)amino,protected (monosubstituted)amino, (disubstituted)amino, carboxamide,protected carboxamide, N-(C₁ to C₁₂ alkyl) carboxamide, protected N-(C₁to C₁₂ alkyl) carboxamide, N, N-di(C₁ to C₁₂ alkyl)carboxamide,trifluoromethyl, N-((C₁ to C₁₂ alkyl)sulfonyl)amino,N-(phenylsulfonyl)amino or a phenyl group, substituted or unsubstituted,for a resulting biphenyl group. The substituted alkyl or phenyl groupsmay be substituted with one or more, and preferably one or two,substituents which can be the same or different.

[0141] Examples of the term “C₇ to C₁₈ substituted phenylalkoxy” includegroups such as 2-(4-hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy,(2R)-3-phenyl-2-amino-propoxy, (2S)-3-phenyl-2-amino-propoxy,2-indanoxy, 6-phenyl-1-hexanoxy, cinnamyloxy, (+/−)-2-phenyl-1-propoxy,2,2-dimethyl-3-phenyl-1-propoxy and the like.

[0142] The term “phthalimide” means a cyclic imide which is made fromphthalic acid, also called 1,2-benzenedicarboxylic acid. The term“substituted phthalimide” specifies a phthalimide group substituted withone or more, and preferably one or two, moieties chosen from the groupsconsisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ toC₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂acyl, C₁ to C₁₂ acyloxy, carboxy, protected carboxy, carboxymethyl,protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino,protected amino, (monosubstituted) amino, protected (monosubstituted)amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C₁to C₁₂ alkyl)carboxamide, protected N-(C₁ to C₁₂ alkyl)carboxamide, N,N-di(C₁ to C₁₂ alkyl)carboxamide, trifluoromethyl, N-((C₁ to C₁₂alkyl)sulfonyl)amino and N-(phenylsulfonyl)amino.

[0143] Examples of substituted phthalimides include4,5-dichlorophthalimido, 3-fluorophthalimido, 4-methoxyphthalimido,3-methylphthalimido, 4-carboxyphthalimido and the like.

[0144] The term “substituted naphthyl” specifies a naphthyl groupsubstituted with one or more, and preferably one or two, moieties eitheron the same ring or on different rings chosen from the groups consistingof halogen, hydroxy, protected hydroxy, cyano, nitro, C₁ to C₆ alkyl, C₁to C₇ alkoxy, C₁ to C₇ acyl, C₁ to C₇ acyloxy, carboxy, protectedcarboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl,protected hydroxymethyl, amino, protected amino, (monosubstituted)amino,protected (monosubstituted)amino, (disubstituted)amino, carboxamide,protected carboxamide, N-(C₁ to C₁₂ alkyl)carboxamide, protected N-(C₁to C₁₂ alkyl)carboxamide, N, N-di(C₁ to C₁₂ alkyl)carboxamide,trifluoromethyl, N-((C₁ to C₁₂ alkyl)sulfonyl)amino orN-(phenylsulfonyl)amino.

[0145] Examples of the term “substituted naphthyl” includes a mono ordi(halo)naphthyl group such as 1,2, 3,4,5,6,7 or 8-chloronaphthyl,2,6-dichloronaphthyl, 2,5-dichloronaphthyl, 3,4-dichloronaphthyl,1,2,3,4, 5,6,7 or 8-bromonaphthyl, 3,4-dibromonaphthyl,3-chloro-4-fluoronaphthyl, 1,2,3,4,5,6,7 or 8-fluoronaphthyl and thelike; a mono or di(hydroxy)naphthyl group such as 1,2,3,4,5,6,7 or8-hydroxynaphthyl, 2,4-dihydroxynaphthyl, the protected-hydroxyderivatives thereof and the like; a nitronaphthyl group such as 3- or4-nitronaphthyl; a cyanonaphthyl group, for example, 1,2,3,4,5,6,7 or8-cyanonaphthyl; a mono- or di(alkyl)naphthyl group such as 2,3,4,5,6,7or 8-methylnaphthyl, 1,2,4-dimethylnaphthyl, 1,2,3,4,5,6,7 or8-(isopropyl)naphthyl, 1,2,3,4,5,6,7 or 8-ethylnaphthyl, 1,2,3,4,5,6,7or 8-(n-propyl)naphthyl and the like; a mono or di(alkoxy)naphthylgroup, for example, 2,6-dimethoxynaphthyl, 1,2,3,4,5,6,7 or8-methoxynaphthyl, 1,2,3,4,5,6,7 or 8-ethoxynaphthyl, 1,2,3,4,5,6,7 or8-(isopropoxy)naphthyl, 1,2,3,4,5,6,7 or 8-(t-butoxy)naphthyl,3-ethoxy-4-methoxynaphthyl and the like; 1,2,3,4,5,6,7 or8-trifluoromethylnaphthyl; a mono- or dicarboxynaphthyl or (protectedcarboxy)naphthyl group such as 1,2,3,4,5,6,7 or 8-carboxynaphthyl or2,4-di(-protected carboxy)naphthyl; a mono-or di(hydroxymethyl)naphthylor (protected hydroxymethyl)naphthyl such as 1,2,3,4,5,6,7 or8-(protected hydroxymethyl)naphthyl or 3,4-di(hydroxymethyl)naphthyl; amono- or di(amino)naphthyl or (protected amino)naphthyl such as1,2,3,4,5,6,7 or 8-(amino)naphthyl or 2,4-(protected amino)-naphthyl, amono- or di(aminomethyl)naphthyl or (protected aminomethyl)naphthyl suchas 2,3, or 4-(aminomethyl)naphthyl or 2,4-(protectedaminomethyl)-naphthyl; or a mono- or di-(N-methylsulfonylamino) naphthylsuch as 1,2,3,4,5,6,7 or 8-(N-methylsulfonylamino)naphthyl. Also, theterm “substituted naphthyl” represents disubstituted naphthyl groupswherein the substituents are different, for example,3-methyl-4-hydroxynaphth-1-yl, 3-chloro-4-hydroxynaphth-2-yl,2-methoxy-4-bromonaphth-1-yl, 4-ethyl-2-hydroxynaphth-1-yl,3-hydroxy-4-nitronaphth-2-yl, 2-hydroxy-4-chloronaphth-1-yl,2-methoxy-7-bromonaphth-1-yl, 4-ethyl-5-hydroxynaphth-2-yl,3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-1-yl and thelike.

[0146] The term “naphthylene” means a naphthyl radical bonded at twopositions connecting together two separate additional groups. Similarly,the term “substituted napthylene” means a naphthylene group that isfurther substituted by halogen, hydroxy, protected hydroxy, C₁ to C₁₀alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀substituted alkylthio, C₁ to C₁₀ substituted alkylsulfoxide, C₁ to C₁₀substituted alkylsulfonyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂substituted alkyl, C₁ to C₁₂ alkoxy, oxo, protected oxo,(monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy,protected carboxy, phenyl, substituted phenyl, phenylthio,phenylsulfoxide, phenylsulfonyl, amino, or protected amino group.

[0147] The terms “halo” and “halogen” refer to the fluoro, chloro, bromoor iodo atoms. There can be one or more halogens, which are the same ordifferent. Preferred halogens are chloro and fluoro.

[0148] The term “(monosubstituted)amino” refers to an amino group withone substituent chosen from the group consisting of phenyl, substitutedphenyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ acyl, C₁to C₁₂ substituted acyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substitutedalkenyl, C₂ to C₁₂ alkynyl, C₂ to C₁₂ substituted alkynyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, heterocyclic ring,substituted heterocyclic ring, C₁ to C₁₂ heterocycloalkyl and C₁ to C₁₂substituted heterocycloalkyl. The (monosubstituted)amino canadditionally have an amino-protecting group as encompassed by the term“protected (monosubstituted)amino.”

[0149] The term “(disubstituted)amino” refers to an amino group with twosubstituents chosen from the group consisting of phenyl, substitutedphenyl, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₁ to C₁₂ acyl, C₂to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl and C₁ to C₁₂substituted heterocycloalkyl. The two substituents can be the same ordifferent.

[0150] The term “amino-protecting group” as used herein refers tosubstituents of the amino group commonly employed to block or protectthe amino functionality while reacting other functional groups of themolecule. The term “protected (monosubstituted)amino” means there is anamino-protecting group on the monosubstituted amino nitrogen atom. Inaddition, the term “protected carboxamide” means there is anamino-protecting group on the carboxamide nitrogen. Similarly, the term“protected N-(C₁ to C₁₂ alkyl)carboxamide” means there is anamino-protecting group on the carboxamide nitrogen.

[0151] Examples of such amino-protecting groups include the formyl(“For”) group, the trityl group, the phthalimido group, thetrichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetylgroups, urethane-type blocking groups, such as t-butoxycarbonyl (“Boc”),2-(4-biphenylyl)propyl-2-oxycarbonyl (“Bpoc”),2-phenylpropyl-2-oxycarbonyl (“Poc”), 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenylethyl-1-oxycarbonyl, 1,1-diphenylpropyl-1-oxycarbonyl,2-(3,5-dimethoxyphenyl)propyl-2-oxycarbonyl (“Ddz”),2-(p-toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl,1-methylcyclopentanyloxycarbonyl, cyclohexanyloxy-carbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)-ethoxycarbonyl, 9-fluorenylmethoxycarbonyl(“Fmoc”), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl-oxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, isobornyloxycarbonyl,1-piperidyloxycarbonyl, benzyloxycarbonyl (“Cbz”),4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy-carbonyl,-2,4,5,-tetramethylbenzyloxycarbonyl (“Tmz”),4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,4-(decyloxy)benzyloxycarbonyl and the like; the benzoylmethylsulfonylgroup, dithiasuccinoyl (“Dts”), the 2-(nitro)phenylsulfenyl group(“Nps”), the diphenyl-phosphine oxide group and like amino-protectinggroups. The species of amino-protecting group employed is not criticalso long as the derivatized amino group is stable to the conditions ofthe subsequent reaction(s) and can be removed at the appropriate pointwithout disrupting the remainder of the compounds. Preferredamino-protecting groups are Boc, Cbz and Fmoc. Further examples ofamino-protecting groups embraced by the above term are well known inorganic synthesis and the peptide art and are described by, for example,T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter7, M. Bodanzsky, “Principles of Peptide Synthesis,” 1st and 2nd reviseded., Springer-Verlag, New York, N.Y., 1984 and 1993, and Stewart andYoung, “Solid Phase Peptide Synthesis,” 2nd ed., Pierce Chemical Co.,Rockford, Ill., 1984, each of which is incorporated herein by reference.The related term “protected amino” defines an amino group substitutedwith an amino-protecting group discussed above.

[0152] The term “protected guanidino” as used herein refers to an“amino-protecting group” on one or two of the guanidino nitrogen atoms.Examples of “protected guanidino” groups are described by T. W. Greeneand P. G. M. Wuts; M. Bodanzsky; and Stewart and Young, supra.

[0153] The term “epimino” means —NH—. The term “substituted epimino”means —N(R)—, where R is a substitution group listed above under thedefinition of “(monosubstituted)amino.”

[0154] The term “C₁ to C₅ alkylene epimino” refers to a one to fivecarbon alkylene chain with an epimino at any point along the chain. Theterm “C₁ to C₅ substituted alkylene epimino” refers to a C₁ to C₅alkylene epimino group that is substituted a) at the epimino position(in the same way as “substituted epimino,” described above); and/or b)at one or more of the alkylene positions (in the same way as“substituted alkylene,” as described above).

[0155] The term “thio” refers to -SH or, if between two other groups,—S—. The term “C₁ to C₁₀ alkylene thio” refers to a one to ten carbonalkylene chain with a thio at any point along the chain. The term “C₁ toC₁₀ substituted alkylene thio” refers to a C₁ to C₁₀ alkylene thio groupthat is substituted at one or more of the alkylene positions (in thesame way as “substituted alkylene,” as described above).

[0156] The term “sulfonyl” refers to —S(O)₂—. The term “C₁ to C₁₀alkylene sulfonyl” refers to a one to ten carbon alkylene chain with asulfonyl at any point along the chain. The term “C₁ to C₁₀ substitutedalkylene sulfonyl” refers to a C₁ to C₁₀ alkylene sulfonyl group that issubstituted at one or more of the alkylene positions (in the same way as“substituted alkylene,” as described above).

[0157] The term “sulfinyl” refers to —S(O)—. The term “C₁ to C₁₀alkylene sulfinyl” refers to a one to ten carbon alkylene chain with asulfinyl at any point along the chain. The term “C₁ to C₁₀ substitutedalkylene sulfinyl” refers to a C₁ to C₁₀ alkylene sulfinyl group that issubstituted at one or more of the alkylene positions (in the same way as“substituted alkylene,” as described above).

[0158] The term “oxy” refers to —O'1. The terms “C₁ to C₁₀ alkyleneoxy,” “C₁ to C₁₀ alkylene dioxy” and “C₁ to C₁₀ alkylene trioxy” referto a one to ten carbon alkylene chain with, respectively, one, two orthree —O— at any point along the chain, provided that no two oxygenatoms are consecutive, and provided that any two oxygen atoms areseparated by at least two carbons. The terms “C₁ to C₁₀ substitutedalkylene oxy,” “C₁ to C₁₀ substituted alkylene dioxy” and “C₁ to C₁₀substituted alkylene trioxy” refer, respectfully to “C₁ to C₁₀ alkyleneoxy,” “C₁ to C₁₀ alkylene dioxy” and “C₁ to C₁₀ alkylene trioxy” thatare substituted at one or more of the alkylene positions (in the sameway as “substituted alkylene,” as described above).

[0159] The term “thiocarbonyl” refers to —C(S)H or, if between two othergroups, —C(S)—. The term “thioester” refers to —C(O)SH or, if betweentwo other groups, —C(O) S—.

[0160] The term “carboxy-protecting group” as used herein refers to oneof the ester derivatives of the carboxylic acid group commonly employedto block or protect the carboxylic acid group while reactions arecarried out on other functional groups on the compound. Examples of suchcarboxylic acid protecting groups include t-butyl, 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxytrityl,4,4′,4″-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl,t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl,(trimethylsilyl)ethyl, (di(n-butyl)methylsilyl)ethyl,p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)propenyl and like moieties. The species ofcarboxy-protecting group employed is not critical so long as thederivatized carboxylic acid is stable to the conditions of subsequentreaction(s) and can be removed at the appropriate point withoutdisrupting the remainder of the molecule. Further examples of thesegroups are found in E. Haslam, “Protective Groups in Organic Chemistry,”J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, andT. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter5, each of which is incorporated herein by reference. A related term is“protected carboxy,” which refers to a carboxy group substituted withone of the above carboxy-protecting groups.

[0161] The term “hydroxy-protecting group” refers to readily cleavablegroups bonded to hydroxyl groups, such as the tetrahydropyranyl,2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl,methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl,4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, benzyl, allyl,trimethylsilyl, (t-butyl)dimethylsilyl, 2,2,2-trichloroethoxycarbonylgroups and the like. The species of hydroxy-protecting groups is notcritical so long as the derivatized hydroxyl group is stable to theconditions of subsequent reaction(s) and can be removed at theappropriate point without disrupting the remainder of the molecule.Further examples of hydroxy-protecting groups are described by C. B.Reese and E. Haslam, “Protective Groups in Organic Chemistry,” J. G. W.McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4,respectively, and T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis,” 2nd ed., John Wiley and Sons, New York, N.Y., 1991,Chapters 2 and 3. Related terms are “protected hydroxy,” and “protectedhydroxymethyl” which refer to a hydroxy or hydroxymethyl substitutedwith one of the above hydroxy-protecting groups.

[0162] The term “C₁ to C₁₀ alkylthio” refers to sulfide groups such asmethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,t-butylthio and like groups. The term “C₁ to C₁₀ alkylsulfoxide”indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide,n-propylsulfoxide, isopropylsulfoxide, n-butylsulfoxide,sec-butylsulfoxide and the like. The term “C₁ to C₁₀ alkylsulfonyl”encompasses groups such as methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyland the like. it should also be understood that the above thio,sulfoxide or sulfonyl groups can be at any point on the alkyl chain(e.g., 2-methylmercaptoethyl).

[0163] The terms “C₁ to C₁₀ substituted alkylthio,” “C₁ to C₁₀substituted alkylsulfoxide,” and “C₁ to C₁₀ substituted alkylsulfonyl,”denote the C₁ to C₁₀ alkyl portion of these groups may be substituted asdescribed above in relation to “substituted alkyl.”

[0164] The terms “phenylthio,” “phenylsulfoxide,” and “phenylsulfonyl”specify a thiol, a sulfoxide, or sulfone, respectively, containing aphenyl group. The terms “substituted phenylthio,” “substitutedphenylsulfoxide,” and “substituted phenylsulfonyl” means that the phenylof these groups can be substituted as described above in relation to“substituted phenyl.”

[0165] The term “C₁ to C₁₂ alkylaminocarbonyl” means a C₁ to C₁₂ alkylattached to a nitrogen of the aminocarbonyl group. Examples of C₁ to C₁₂alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl,propylaminocarbonyl and butylaminocarbonyl. The term “C₁ to C₁₂substituted alkylaminocarbonyl” denotes a substituted alkyl bonded to anitrogen of the aminocarbonyl group, which alkyl may be substituted asdescribed above in relation to C₁ to C₁₂ substituted alkyl. Examples ofC₁ to C₁₂ substituted alkylaminocarbonyl include, for example,methoxymethylaminocarbonyl, 2-chloroethylaminocarbonyl,2-oxopropylaminocarbonyl and 4-phenylbutylaminocarbonyl.

[0166] The term “C₁ to C₁₂ alkoxycarbonyl” means a “C₁ to C₁₂ alkoxy”group attached to a carbonyl group. The term “C₁ to C₁₂ substitutedalkoxycarbonyl” denotes a substituted alkoxy bonded to the carbonylgroup, which alkoxy may be substituted as described above in relation to“C₁ to C₁₂ substituted alkyl.”

[0167] The term “phenylaminocarbonyl” means a phenyl attached to anitrogen of the aminocarbonyl group. The term “substitutedphenylaminocarbonyl” denotes a substituted phenyl bonded to a nitrogenof the aminocarbonyl group, which phenyl may be substituted as describedabove in relation to substituted phenyl. Examples of substitutedphenylaminocarbonyl include 2-chlorophenylaminocarbonyl,3-chlorophenylaminocarbonyl, 2-nitorphenylaminocarbonyl,4-biphenylaminocarbonyl, and 4-methoxyphenylaminocarbonyl.

[0168] The term “C₁ to C₁₂ alkylaminothiocarbonyl” means a C₁ to C₁₂alkyl attached to an aminothiocarbonyl group, wherein the alkyl has thesame meaning as defined above. Examples of C₁ to C₁₂alkylaminothiocarbonyl include methylaminothiocarbonyl,ethylaminothiocarbonyl, propylaminothiocarbonyl andbutylaminothiocarbonyl.

[0169] The term “C₁ to C₁₂ substituted alkylaminothiocarbonyl” denotes asubstituted alkyl bonded to an aminothiocarbonyl group, wherein thealkyl may be substituted as described above in relation to C₁ to C₁₂substituted alkyl. Examples of C₁ to C₁₂ substitutedalkylaminothiocarbonyl include, for example,methoxymethylaminothiocarbonyl, 2-chloroethylaminothiocarbonyl,2-oxopropylaminothiocarbonyl and 4-phenylbutylaminothiocarbonyl.

[0170] The term “phenylaminothiocarbonyl” means a phenyl attached to anaminothiocarbonyl group, wherein the phenyl has the same meaning asdefined above.

[0171] The term “substituted phenylaminothiocarbonyl” denotes asubstituted phenyl bonded to an aminothiocarbonyl group, wherein phenylmay be substituted as described above in relation to substituted phenyl.Examples of substituted phenylaminothiocarbonyls include2-chlorophenylaminothiocarbonyl, 3-chlorophenylaminothiocarbonyl,2-nitorphenylaminothiocarbonyl, 4-biphenylaminothiocarbonyl and4-methoxyphenylaminothiocarbonyl.

[0172] The term “phenylene” means a phenyl group where the phenylradical is bonded at two positions connecting together two separateadditional groups. Examples of “phenylene” include 1,2-phenylene,1,3-phenylene, and 1,4-phenylene.

[0173] The term “substituted phenylene” means a phenyl group where thephenyl radical is bonded at two positions connecting together twoseparate additional groups, wherein the phenyl is substituted asdescribed above in relation to “substituted phenyl.”

[0174] The term “substituted C₁ to C₁₂ alkylene” means a C₁ to C₁₂ alkylgroup where the alkyl radical is bonded at two positions connectingtogether two separate additional groups and further bearing anadditional substituent. Examples of “substituted C₁ to C₁₂ alkylene”includes aminomethylene, 1-(amino)-1,2-ethyl, 2-(amino)-1,2-ethyl,1-(acetamido)-1,2-ethyl, 2-(acetamido)-1,2-ethyl, 2-hydroxy-1,1-ethyl,1-(amino)-1,3-propyl.

[0175] The terms “cyclic C₂ to C₇ alkylene,” “substituted cyclic C₂ toC₇ alkylene,” “cyclic C₂ to C₇ heteroalkylene,” and “substituted cyclicC₂ to C₇ heteroalkylene,” defines such a cyclic group bonded (“fused”)to the phenyl radical resulting in a bicyclic ring system. The cyclicgroup may be saturated or contain one or two double bonds. Furthermore,the cyclic group may have one or two methylene or methine groupsreplaced by one or two oxygen, nitrogen or sulfur atoms which are thecyclic C₂ to C₇ heteroalkylene.

[0176] The cyclic alkylene or heteroalkylene group may be substitutedonce or twice by the same or different substituents which, ifappropriate, can be connected to another part of the compound (e.g.,alkylene) selected from the group consisting of the following moieties:hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protectedoxo, C₁ to C₄ acyloxy, formyl, C₁ to C₁₂ acyl, C₁ to C₁₂ alkyl, C₁ to C₇alkoxy, C₁ to C₁₀ alkylthio, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀alkylsulfonyl, halo, amino, protected amino, (monosubstituted)amino,protected (monosubstituted) amino, (disubstituted) amino, hydroxymethylor a protected hydroxymethyl.

[0177] The cyclic alkylene or heteroalkylene group fused onto thebenzene radical can contain two to ten ring members, but it preferablycontains three to six members. Examples of such saturated cyclic groupsare when the resultant bicyclic ring system is 2,3-dihydroindanyl and atetralin ring. When the cyclic groups are unsaturated, examples occurwhen the resultant bicyclic ring system is a naphthyl ring or indolyl.Examples of fused cyclic groups which each contain one nitrogen atom andone or more double bond, preferably one or two double bonds, are whenthe benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl,dihydropyrrolo, or dihydropyridinyl ring. Examples of fused cyclicgroups which each contain one oxygen atom and one or two double bondsare when the benzene radical ring is fused to a furo, pyrano,dihydrofurano, or dihydropyrano ring. Examples of fused cyclic groupswhich each have one sulfur atom and contain one or two double bonds arewhen the benzene radical is fused to a thieno, thiopyrano, dihydrothienoor dihydrothiopyrano ring. Examples of cyclic groups which contain twoheteroatoms selected from sulfur and nitrogen and one or two doublebonds are when the benzene radical ring is fused to a thiazolo,isothiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples ofcyclic groups which contain two heteroatoms selected from oxygen andnitrogen and one or two double bonds are when the benzene ring is fusedto an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring.Examples of cyclic groups which contain two nitrogen heteroatoms and oneor two double bonds occur when the benzene ring is fused to a pyrazolo,imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl.

[0178] The term “carbamoyl” means an —NC(O)— group where the radical isbonded at two positions connecting two separate additional groups.

[0179] One or more of the compounds of the invention, even within agiven library, may be present as a salt. The term “salt” encompassesthose salts that form with the carboxylate anions and amine nitrogensand include salts formed with the organic and inorganic anions andcations discussed below. Furthermore, the term includes salts that formby standard acid-base reactions with basic groups (such as amino groups)and organic or inorganic acids. Such acids include hydrochloric,hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic,citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic,D-glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic,salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic,cinnamic, and like acids.

[0180] The term “organic or inorganic cation” refers to counter-ions forthe carboxylate anion of a carboxylate salt. The counter-ions are chosenfrom the alkali and alkaline earth metals, (such as lithium, sodium,potassium, barium, aluminum and calcium); ammonium and mono-, di- andtri-alkyl amines such as trimethylamine, cyclohexylamine; and theorganic cations, such as dibenzylammonium, benzylammonium,2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium,phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.See, for example, “Pharmaceutical Salts,” Berge et al., J. Pharm. Sci.,66:1-19 (1977), which is incorporated herein by reference. Other cationsencompassed by the above term include the protonated form of procaine,quinine and N-methylglucosamine, and the protonated forms of basic aminoacids such as glycine, ornithine, histidine, phenylglycine, lysine andarginine. Furthermore, any zwitterionic form of the instant compoundsformed by a carboxylic acid and an amino group is referred to by thisterm. For example, a cation for a carboxylate anion will exist when aposition is substituted with a (quaternary ammonium)methyl group. Apreferred cation for the carboxylate anion is the sodium cation.

[0181] The compounds of the invention can also exist as solvates andhydrates. Thus, these compounds may crystallize with, for example,waters of hydration, or one, a number of, or any fraction thereof ofmolecules of the mother liquor solvent. The solvates and hydrates ofsuch compounds are included within the scope of this invention.

[0182] One or more compounds of the invention, even when in a library,can be in the biologically active ester form, such as the non-toxic,metabolically-labile ester-form. Such ester forms induce increased bloodlevels and prolong the efficacy of the corresponding non-esterifiedforms of the compounds. Ester groups which can be used include the loweralkoxymethyl groups, for example, methoxymethyl, ethoxymethyl,isopropoxymethyl and the like; the —(C₁ to C₁₂) alkoxyethyl groups, forexample methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl and thelike; the 2-oxo-1,3-diooxlen-4-ylmethyl groups, such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl,5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl and the like; the C₁ to C₁₀alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl,iso-propylthiomethyl and the like; the acyloxymethyl groups, for examplepivaloyloxymethyl, pivaloyloxyethyl, -acetoxymethyl and the like; theethoxycarbonyl-1-methyl group; the acetoxyethyl; the 1 (C₁ to C₁₂alkyloxycarbonyloxy)ethyl groups such as the 1-(ethoxycarbonyloxy)ethylgroup; and the 1-(C₁ to C₁₂ alkylaminocarbonyloxy)ethyl groups such asthe 1-(methylaminocarbonyloxy)ethyl group.

[0183] The term “amino acid” includes any one of the twentynaturally-occurring amino acids or the D-form of any one of thenaturally-occurring amino acids. In addition, the term “amino acid” alsoincludes other non-naturally occurring amino acids besides the D-aminoacids, which are functional equivalents of the naturally-occurring aminoacids. Such non-naturally-occurring amino acids include, for example,norleucine (“Nle”), norvaline (“Nva”), L- or D- naphthalanine, ornithine(“Orn”), homoarginine (homoArg) and others well known in the peptideart, such as those described in M. Bodanzsky, “Principles of PeptideSynthesis,” 1st and 2nd revised ed., Springer-Verlag, New York, N.Y.,1984 and 1993, and Stewart and Young, “Solid Phase Peptide Synthesis,”2nd ed., Pierce Chemical Co., Rockford, Ill., 1984, both of which areincorporated herein by reference. Amino acids and amino acid analogs canbe purchased commercially (Sigma Chemical Co.; Advanced Chemtech) orsynthesized using methods known in the art.

[0184] It should be understood that any position of the claimedinvention has up to three serial “substitutions.” For example, a“substituted alkyl” that is substituted with a “substituted phenyl” thatis, in turn, substituted with a “substituted alkyl” can, in turn, besusbstitued by one more group and no longer further substituted.However, it should also be understood that the invention contemplates,if appropriate, more than three parallel susbstitutions. For example, ifappropriate, more than three hydrogens on an alkyl moiety may besubstituted with any one or more of a variety of groups, including haloand hydroxy.

[0185] The term “functionalized resin” means any resin, crosslinked orotherwise, where functional groups have been introduced into the resin,as is common in the art. Such resins include, for example, thosefunctionalized with amino, alkylhalo, formyl or hydroxy groups. Suchresins which can serve as solid supports are well known in the art andinclude, for example, 4-methylbenzhydrylamine-copoly(styrene-1%divinylbenzene) (MBHA), 4-hydroxymethylphenoxymethyl-copoly(styrene-1%divinylbenzene), 4-oxymethyl-phenyl-acetamido-copoly(stryene-1%divinylbenzene)(Wang), 4-(oxymethyl)-phenylacetamido methyl (Pam), andTentagel™, from Rapp Polymere Gmbh, trialkoxy-diphenyl-methylester-copoly(styrene-1% divinylbenzene)(RINK) all of which arecommercially available. Other functionalized resins are known in the artand can be use without departure from the scope of the currentinvention. Such resins may include those described in Jung, G.,Combinatorial Peptide and Nonpeptide Libraries, A Handbook (VCH Verlag,1996) or Bunin, B. A., The Combinatorial Index (Academic Press, 1998)and are incorporated herein by reference.

[0186] As used herein, a “combinatorial library” is an intentionallycreated collection of differing molecules which can be prepared by themeans provided below or otherwise and screened for biological activityin a variety of formats (e.g., libraries of soluble molecules, librariesof compounds attached to resin beads, silica chips or other solidsupports). A “combinatorial library,” as defined above, involvessuccessive rounds of chemical syntheses based on a common startingstructure. The combinatorial libraries can be screened in any variety ofassays, such as those detailed below as well as others useful forassessing their biological activity. The combinatorial libraries willgenerally have at least one active compound and are generally preparedsuch that the compounds are in equimolar quantities.

[0187] Compounds disclosed in previous work that are not disclosed aspart of a collection of compounds or not disclosed as intended for useas part of such a collection are not part of a “combinatorial library”of the invention. In addition, compounds that are in an unintentional orundesired mixture are not part of a “combinatorial library” of theinvention.

[0188] A combinatorial library of the invention can contain two or moreof the above-described compounds. The invention further provides acombinatorial library containing three, four or five or more of theabove-described compounds. In another embodiment of the invention, acombinatorial library can contain ten or more of the above-describedcompounds. In yet another embodiment of the invention, a combinatoriallibrary can contain fifty or more of the above-described compounds. Ifdesired, a combinatorial library of the invention can contain 100,000 ormore, or even 1,000,000 or more, of the above-described compounds.

[0189] By way of example, the preparation of the combinatorial librariescan use the “split resin approach.” The split resin approach isdescribed by, for example, U.S. Pat. No. 5,010,175 to Rutter, WO PCT91/19735 to Simon, and Gallop et al., J. Med. Chem., 37:1233-1251(1994), all of which are incorporated herein by reference.

[0190] The amino acids are indicated herein by either their full name orby the commonly known three letter code. Further, in the naming of aminoacids, “D-” designates an amino acid having the “D” configuration, asopposed to the naturally occurring L-amino acids. Where no specificconfiguration is indicated, one skilled in the art would understand theamino acid to be an L-amino acid. The amino acids can, however, also bein racemic mixtures of the D- and L-configuration or the D-amino acidcan readily be substituted for that in the L-configuration.

[0191] For preparing pharmaceutical compositions containing compounds ofthe invention, inert, pharmaceutically acceptable carriers are used. Thepharmaceutical carrier can be either solid or liquid. Solid formpreparations include, for example, powders, tablets, dispersiblegranules, capsules, cachets, and suppositories.

[0192] A solid carrier can be one or more substances which can also actas diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, or tablet disintegrating agents; it can also be anencapsulating material.

[0193] In powders, the carrier is generally a finely divided solid whichis in a mixture with the finely divided active component. In tablets,the active compound is mixed with the carrier having the necessarybinding properties in suitable proportions and compacted in the shapeand size desired.

[0194] For preparing pharmaceutical composition in the form ofsuppositories, a low-melting wax such as a mixture of fatty acidglycerides and cocoa butter is first melted and the active ingredient isdispersed therein by, for example, stirring. The molten homogeneousmixture is then poured into convenient-sized molds and allowed to cooland solidify.

[0195] Powders and tablets preferably contain between about 5% to about70% by weight of the active ingredient. Suitable carriers include, forexample, magnesium carbonate, magnesium stearate, talc, lactose, sugar,pectin, dextrin, starch, tragacanth, methyl cellulose, sodiumcarboxymethyl cellulose, a low-melting wax, cocoa butter and the like.

[0196] The pharmaceutical compositions can include the formulation ofthe active compound with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier, which is thus in association with it. In asimilar manner, cachets are also included. Tablets, powders, cachets,and capsules can be used as solid dosage forms suitable for oraladministration.

[0197] Liquid pharmaceutical compositions include, for example,solutions suitable for oral or parenteral administration, orsuspensions, and emulsions suitable for oral administration. Sterilewater solutions of the active component or sterile solutions of theactive component in solvents comprising water, ethanol, or propyleneglycol are examples of liquid compositions suitable for parenteraladministration.

[0198] Sterile solutions can be prepared by dissolving the activecomponent in the desired solvent system, and then passing the resultingsolution through a membrane filter to sterilize it or, alternatively, bydissolving the sterile compound in a previously sterilized solvent understerile conditions.

[0199] Aqueous solutions for oral administration can be prepared bydissolving the active compound in water and adding suitable flavorants,coloring agents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural or synthetic gums, resins, methyl cellulose, sodiumcarboxymethyl cellulose, and other suspending agents known to thepharmaceutical formulation art.

[0200] Preferably, the pharmaceutical composition is in unit dosageform. In such form, the composition is divided into unit dosescontaining appropriate quantities of the active 2-aminobenzoxazolecompound. The unit dosage form can be a packaged preparation, thepackage containing discrete quantities of the preparation, for example,packeted tablets, capsules, and powders in vials or ampules. The unitdosage form can also be a capsule, cachet, or tablet itself, or it canbe the appropriate number of any of these packaged forms.

[0201] As pharmaceutical compositions for treating infections, pain, orany other indication the compounds of the present invention aregenerally in a pharmaceutical composition so as to be administered to asubject at dosage levels of from 0.7 to 7000 mg per day, and preferably1 to 500 mg per day, for a normal human adult of approximately 70 kg ofbody weight, this translates into a dosage of from 0.01 to 100 mg/kg ofbody weight per day. The specific dosages employed, however, can bevaried depending upon the requirements of the patient, the severity ofthe condition being treated, and the activity of the compound beingemployed. The determination of optimum dosages for a particularsituation is within the skill of the art.

[0202] 2-aminobenzoxazole derivative compounds and libraries, such asthose of the present invention, can be made utilizing individualpolyethylene bags, referred to as “tea bags” (see Houghten et al., Proc.Natl. Acad. Sci. USA 82: 5131 (1985); Biochemistry, 32:11035 (1993); andU.S. Pat. No. 4,631,211, all of which are incorporated herein byreference).

[0203] The nonsupport-bound combinatorial libraries can be screened assingle compounds. In addition, the nonsupport-bound combinatoriallibraries can be screened as mixtures in solution in assays such asradio-receptor inhibition assays, anti-bacterial assays, anti-fungalassays, calmodulin-dependent phosphodiesterase (CaMPDE) assays andphosphodiesterase (PDE) assays, as described in detail below.Deconvolution of highly active mixtures can then be carried out byiterative or positional scanning methods. These techniques, theiterative approach or the positional scanning approach, can be utilizedfor finding other active compounds within the combinatorial libraries ofthe present invention using any one of the below-described assays orothers well known in the art.

[0204] The iterative approach is well-known and is set forth in generalin Houghten et al., Nature, 354, 84-86 (1991) and Dooley et al.,Science, 266, 2019-2022 (1994), both of which are incorporated herein byreference. In the iterative approach, for example, sub-libraries of amolecule having three variable groups are made wherein the firstvariable is defined. Each of the compounds with the defined variablegroup is reacted with all of the other possibilities at the other twovariable groups. These sub-libraries are each tested to define theidentity of the second variable in the sub-library having the highestactivity in the screen of choice. A new sub-library with the first twovariable positions defined is reacted again with all the otherpossibilities at the remaining undefined variable position. As before,the identity of the third variable position in the sub-library havingthe highest activity is determined. If more variables exist, thisprocess is repeated for all variables, yielding the compound with eachvariable contributing to the highest desired activity in the screeningprocess. Promising compounds from this process can then be synthesizedon larger scale in traditional single-compound synthetic methods forfurther biological investigation.

[0205] The positional-scanning approach has been described for variouscombinatorial libraries as described, for example, in R. Houghten et al.PCT/US91/08694 and U.S. Pat. No. 5,556,762, both of which areincorporated herein by reference. In the positional scanning approach,sublibraries are made defining only one variable with each set ofsublibraries and all possible sublibraries with each single variabledefined (and all other possibilities at all of the other variablepositions), made and tested. From the instant description one skilled inthe art could synthesize combinatorial libraries wherein two fixedpositions are defined at a time. From the testing of eachsingle-variable defined combinatorial library, the optimum substituentat that position can be determined, pointing to the optimum or at leasta series of compounds having a maximum of the desired biologicalactivity. Thus, the number of sublibraries for compounds with a singleposition defined will be the number of different substituents desired atthat position, and the number of all the compounds in each sublibrarywill be the product of the number of substituents at each of the othervariables.

[0206] Individual compounds and pharmaceutical compositions containingthe compounds, as well as methods of using the same, are included withinthe scope of the present invention. The compounds of the presentinvention can be used for a variety of purposes and indications and asmedicaments for any such purposes and indications. For example,2-aminobenzoxazole derivative compounds of the present invention can beused as pesticides, acaricides, receptor agonists or antagonists andantimicrobial agents, including antibacterial or antiviral agents. Thelibraries can be screened in any variety of melanocortin receptor andrelated activity assays, such as those detailed below as well as othersknown in the art. Additionally, the subject compounds can be useful asanalgesics. Assays which can be used to test the biological activity ofthe instant compounds include antimicrobial assays, a competitiveenzyme-linked immunoabsorbent assay and radio-receptor assays, asdescribed below.

[0207] The melanocortin (MC) receptors are a group of cell surfaceproteins that mediate a variety of physiological effects, includingregulation of adrenal gland function such as production of theglucocorticoids cortisol and aldosterone; control of melanocyte growthand pigment production; thermoregulation; immunomodulation; andanalgesia. Five distinct MC receptors have been cloned and are expressedin a variety of tissues, including melanocytes, adrenal cortex, brain,gut, placenta, skeletal muscle, lung, spleen, thymus, bone marrow,pituitary, gonads and adipose tissue (Tatro, Neuroimmunomodulation3:259-284 (1996)). Three MC receptors, MCR-1, MCR-3 and MCR-4, areexpressed in brain tissue (Xia et al., Neuroreport 6:2193-2196 (1995)).

[0208] A variety of ligands termed melanocortins function as agoniststhat stimulate the activity of MC receptors. The melanocortins includemelanocyte-stimulating hormones (MSH) such as α-MSH, β-MSH and γ-MSH, aswell as adrenocorticotropic hormone (ACTH). Individual ligands can bindto multiple MC receptors with differing relative affinities. The varietyof ligands and MC receptors with differential tissue-specific expressionlikely provides the molecular basis for the diverse physiologicaleffects of melanocortins and MC receptors. For example, α-MSHantagonizes the actions of immunological substances such as cytokinesand acts to modulate fever, inflammation and immune responses (Cataniaand Lipton, Annals N.Y. Acad. Sci. 680:412-423 (1993)).

[0209] The role of certain specific MC receptors in some of thephysiological effects described above for MC receptors has beenelucidated. For example, MCR-1 is involved in pain and inflammation.MCR-1 mRNA is expressed in neutrophils (Catania et al., Peptides17:675-679 (1996)). The anti-inflammatory agent α-MSH was found toinhibit migration of neutrophils. Thus, the presence of MCR-1 inneutrophils correlates with the anti-inflammatory activity of α-MSH.

[0210] An interesting link of MC receptors to regulation of food intakeand obesity has recently been described. The brain MC receptor MCR-4 hasbeen shown to function in the regulation of body weight and food intake.Mice in which MCR-4 has been knocked out exhibit weight gain (Huszar etal., Cell 88:131-141 (1997)). In addition, injection into brain ofsynthetic peptides that mimic melanocortins and bind to MCR-4 causedsuppressed feeding in normal and mutant obese mice (Fan et al., Nature385:165-168 (1997)). These results indicate that the brain MC receptorMCR-4 functions in regulating food intake and body weight.

[0211] Due to the varied physiological activities of MC receptors, highaffinity ligands of MC receptors could be used to exploit the variedphysiological responses of MC receptors by functioning as potentialtherapeutic agents or as lead compounds for the development oftherapeutic agents. Furthermore, due to the effect of MC receptors onthe activity of various cytokines, high affinity MC receptor ligandscould also be used to regulate cytokine activity.

[0212] A variety of assays can be used to identify or characterize MCreceptor ligands of the invention. For example, the ability of a2-aminobenzoxazole derivative compound to compete for binding of a knownMC receptor ligand can be used to assess the affinity and specificity ofa 2-aminobenzoxazole derivative compound for one or more MC receptors.Any MC receptor ligand can be used so long as the ligand can be labeledwith a detectable moiety. The detectable moiety can be, for example, aradiolabel, fluorescent label or chromophore, or any detectablefunctional moiety so long as the MC receptor ligand exhibits specific MCreceptor binding. A particularly useful detectable MC receptor ligandfor identifying and characterizing other MC receptor ligands is ¹²⁵I-HP467, which has the amino acid sequenceAc-Nle-Gln-His-(p(I)-D-Phe)-Arg-(D-Trp)-Gly-NH₂ and is described inDooley et al., “Melanocortin Receptor Ligands and Methods of UsingSame,” U.S. patent application Ser. No. 09/027,108, filed Feb. 20, 1998,which is incorporated herein by reference. HP 467 is a paraiodinatedform of HP 228.

[0213] Using assay methods such as those described above, bindingkinetics and competition with radiolabeled HP 467 can confirm that2-aminobenzoxazole derivative compounds of the invention bind to one ormore MC receptors. Furthermore, 2-aminobenzoxazole derivative compoundsof the invention can exhibit a range of affinities and specificity forvarious MC receptors.

[0214] The invention provides MC receptor ligands that can bind toseveral MC receptors with similar affinity. In addition, the inventionalso provides MC receptor ligands that can be selective for one or moreMC receptors. As used herein, the term “selective” means that theaffinity of a MC receptor ligand differs between one MC receptor andanother by about 10-fold, generally about 20- to 50-fold, andparticularly about 100-fold. In some cases, a MC receptor ligand havingbroad specificity is desired. In other cases, it is desirable to use MCreceptor ligands having selectivity for a particular MC receptor. Forexample, MCR-1 ligands are particularly useful for treating pain andinflammation, whereas MCR-4 ligands are useful for treating obesity. Thebinding characteristics and specificity of a given MC receptor ligandcan be selected based on the particular disease or physiological effectthat is desired to be altered.

[0215] Another assay useful for identifying or characterizing MCreceptor ligands measures signaling of MC receptors. MC receptors are Gprotein-coupled receptors that couple to adenylate cyclase and producecAMP. Therefore, measuring cAMP production in a cell expressing a MCreceptor and treated with a MC receptor ligand can be used to assess thefunction of the MC receptor ligand in activating a MC receptor.

[0216] Ligands for MC-3 that can alter the activity of an MC-3 receptorcan be useful for treating sexual dysfunction and other conditions orconditions associated with MC-3 such as inflammation. OtherMC-3-associated conditions that can be treated with the MC-3 receptorligands include disuse deconditioning; organ damage such as organtransplantation or ischemic injury; adverse reactions associated withcancer chemotherapy; diseases such as atherosclerosis that are mediatedby free radicals and nitric oxide action; bacterial endotoxic sepsis andrelated shock; adult respiratory distress syndrome; and autoimmune orother patho-immunogenic diseases or reactions such as allergic reactionsor anaphylaxis, rheumatoid arthritis, inflammatory bowel disease,ulcerative colitis, glomerulonephritis, systemic lupus erythematosus,transplant atherosclerosis and parasitic mediated immune dysfunctionssuch as Chagas's disease.

[0217] The invention further provides a method for treating anMC-3-associated condition in a subject. The term “MC-3-associatedcondition” includes any condition or condition mediated by MC-3 or canbe affected by binding an MC-3 ligand. Such conditions includeinflammation and sexual dysfunction.

[0218] The term “sexual dysfunction” herein means any condition thatinhibits or impairs normal sexual function, including coitus. However,the term need not be limited to physiological conditions, but mayinclude psychogenic conditions or perceived impairment without a formaldiagnosis of pathology.

[0219] In males, sexual dysfunction includes erectile dysfunction. Theterm “erectile dysfunction” or “impotence” means herein the inability orimpaired ability to attain or sustain an erection that would be ofsatisfactory rigidity for coitus. Sexual dysfunction in males can alsoinclude premature ejaculation and priapism, which is a condition ofprolonged and sometimes painful erection unrelated to sexual activity,often associated with sickle-cell disease.

[0220] In females, sexual dysfunction includes sexual arousal disorder.The term “sexual arousal disorder” means herein a persistent orrecurrent failure to attain or maintain the lubrication-swellingresponse of sexual excitement until completion of sexual activity.Sexual dysfunction in females can also include inhibited orgasm anddyspareunia, which is painful or difficult coitus. Sexual dysfunctioncan also be manifested as inhibited sexual desire or inhibited lordosisbehavior in animals.

[0221] In addition, the ability of the compounds to inhibit bacterialgrowth, and therefore be useful to that infection, can be determined bymethods well known in the art. Compounds of the present invention can beshown to have antimicrobial activity by the in vitro antimicrobialactivity assay described below and, therefore, are useful asantimicrobial agents.

[0222] Moreover, an exemplary in vitro antimicrobial activity assay isdescribed in Blondelle and Houghten, Biochemistry 30:4671-4678 (1991),which is incorporated herein by reference. In brief, Staphylococcusaureus ATCC 29213 (Rockville, Md.) is grown overnight at 37 C. inMueller-Hinton broth, then re-inoculated and incubated at 37 C. to reachthe exponential phase of bacterial growth (i.e., a final bacterialsuspension containing 10⁵ to 5×10⁵ colony-forming units/ml). Theconcentration of cells is established by plating 100 μl of the culturesolution using serial dilutions (e.g., 10⁻², 10⁻³ and 10⁻⁴) onto solidagar plates. In 96-well tissue culture plates, compounds, individual orin mixtures, are added to the bacterial suspension at concentrationsderived from serial two-fold dilutions ranging from 1500 to 2.9 μg/ml.The plates are incubated overnight at 37 C. and the growth determined ateach concentration by OD₆₂₀ nm. The IC₅₀ (the concentration necessary toinhibit 50% of the growth of the bacteria) can then be calculated.

[0223] The competitive ELISA method which can be used here is amodification of the direct ELISA technique described previously in Appelet al., J. Immunol. 144:976-983 (1990), which is incorporated herein byreference. It differs only in the MAb addition step. Briefly, multi-wellmicroplates are coated with an antigenic peptide at a concentration of100 pmol/50 μl. After blocking, 25 μl of a 1.0 mg/ml solution of eachmixture of a synthetic combinatorial library (or individual compound) isadded, followed by MAb 125-10 F3 (Appel et al., supra) (25 μl per well).The MAb is added at a fixed dilution in which the bicyclic guanidine insolution effectively competes for MAb binding with the antigenic peptideadsorbed to the plate. The remaining steps are the same as for directELISA. The concentration of compound necessary to inhibit 50% of the MAbbinding to the control peptide on the plate (IC₅₀) is determined byserial dilutions of the compound.

[0224] Alternative screening can be done with radio-receptor assays. Theradio-receptor assay, can be selective for any one of the μ, κ, or δopiate receptors. Compounds of the present invention can be useful invitro for the diagnosis of relevant opioid receptor subtypes, such as κ,in the brain and other tissue samples. Similarly, the compounds can beused in vivo diagnostically to localize opioid receptor subtypes.

[0225] The radio-receptor assays are also an indication of thecompounds' analgesic properties as described, for example, in Dooley etal., Proc. Natl. Acad. Sci., 90:10811-10815 (1993). For example, it canbe envisioned that these compounds can be used for therapeutic purposesto block the peripheral effects of a centrally acting pain killer. Forinstance, morphine is a centrally acting pain killer. Morphine, however,has a number of deleterious effects in the periphery which are notrequired for the desired analgesic effects, such as constipation andpruritus (itching). While it is known that the many compounds do notreadily cross the blood-brain barrier and, therefore, elicit no centraleffect, the subject compounds can have value in blocking the peripheryeffects of morphine, such as constipation and pruritus. Accordingly, thesubject compounds can also be useful as drugs, namely as analgesics, orto treat pathologies associated with other compounds which interact withthe opioid receptor system.

[0226] Additionally, such compounds can be tested in a σ receptor assay.Ligands for the σ receptor can be useful as antipsychotic agents, asdescribed in Abou-Gharbia et al., Annual Reports in Medicinal Chemistry,28:1-10 (1993).

[0227] Radio-receptor assays can be performed with particulate membranesprepared using a modification of the method described in Pasternak etal., Mol. Pharmacol. 11:340-351 (1975), which is incorporated herein byreference. Rat brains frozen in liquid nitrogen can be obtained fromRockland (Gilbertsville, Pa.). The brains are thawed, the cerebellaremoved and the remaining tissue weighed. Each brain is individuallyhomogenized in 40 ml Tris-HCl buffer (50 mM, pH 7.4, 4 C) andcentrifuged (Sorvall® RC₅C SA-600: Du Pont, Wilmington, Del.) (16,000rpm) for 10 minutes. The pellets are resuspended in fresh Tris-HC₁buffer and incubated at 37 C. for 40 minutes. Following incubation, thesuspensions are centrifuged as before, the resulting pellets resuspendedin 100 volumes of Tris buffer and the suspensions combined. Membranesuspensions are prepared and used in the same day. Protein content ofthe crude homogenates generally range from 0.15-0.2 mg/ml as determinedusing the method described in Bradford, M. M., Anal. Biochem. 72:248-254(1976), which is incorporated herein by reference.

[0228] Binding assays are carried out in polypropylene tubes, each tubecontaining 0.5 ml of membrane suspension. 8 nM of DAMGO (specificactivity=36 Ci/mmol, 160,000 cpm per tube; which can be obtained fromMultiple Peptide Systems, San Diego, Calif., through NIDA drugdistribution program 271-90-7302) and 80 μg/ml of the subject compound,individual or as a mixture, and Tris-HCl buffer in a total volume of0.65 ml. Assay tubes are incubated for 60 mins. at 25 C. The reaction isterminated by filtration through GF-B filters on a Tomtec harvester(Orange, Conn.). The filters are subsequently washed with 6 ml ofTris-HCl buffer, 4 C. Bound radioactivity is counted on a PharmaciaBiotech Betaplate Liquid Scintillation Counter (Piscataway, N.J.) andexpressed in cpm. To determine inter- and intra-assay variation,standard curves in which ³H-DAMGO is incubated in the presence of arange of concentrations of unlabeled DAMGO (0.13-3900 nM) are generallyincluded in each plate of each assay (a 96-well format). Competitiveinhibition assays are performed as above using serial dilutions of thebicyclic guanidines, individually or in mixtures. IC₅₀ values (theconcentration necessary to inhibit 50% of ³H-DAMGO binding) are thencalculated. IC₅₀ values of less than 1000 nM are indicative of highlyactive opioid compounds which bind to the μ receptor, with particularlyactive compounds having IC₅₀ values of 100 nM or less and the mostactive compounds with values of less than 10 nM.

[0229] As opposed to this μ receptor selective assay, which can becarried out using ³H-DAMGO as radioligand, as described above, assaysselective for κ receptors can be carried out using [³H]-U69,593 (3 nM,specific activity 62 Ci/mmol) as radioligand. Assays selective for δopiate receptors can be carried out using tritiated DSLET ([D-Ser²,D-Leu⁵]-threonine-enkephalin) as radioligand. Assays selective for the aopiate receptor can use radiolabeled pentazocine as ligand.

[0230] Screening of combinatorial libraries and compounds of theinvention can be done with an anti-fungal assay. Compounds of thepresent invention can be useful for treating fungal infections.

[0231] Screening of combinatorial libraries and compounds of theinvention also can be done with a calmodulin-dependent phosphodiesterase(CaMPDE) assay. Compounds of the present invention can be useful ascalmodulin antagonists.

[0232] Calmodulin (CaM), which is the major intracellular calciumreceptor, is involved in many processes that are crucial to cellularviability. In particular, calmodulin is implicated in calcium-stimulatedcell proliferation. Calmodulin antagonists are, therefore, useful fortreating conditions associated with increased cell proliferation, forexample, cancer. In addition, calmodulin antagonists such as compoundsof the subject invention are useful both in vitro and in vivo foridentifying the role of calmodulin in other biological processes. Thedisadvantages of known antagonists such as trifluoperazine andN-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide (W13) include theirnon-specificity and toxicity. In contrast, advantages of thecombinatorial libraries and compounds of the subject invention ascalmodulin antagonists include their reduced flexibility and ability togenerate broader conformational space of interactive residues ascompared to their linear counterparts.

[0233] An example of an assay that identifies CaM antagonists is aCaMPDE assay. In brief, samples are mixed with 50 μl of assay buffer(360 mM Tris, 360 mM Imidazole, 45 mM Mg(CH₃COO)₂, pH 7.5) and 10 μl ofCaCl₂ (4.5 mM) to a final volume of 251 μl. 25 μl of calmodulin stocksolution (Boehringer Mannheim; 0.01 μg/μl) is then added and the samplesthen sit at room temperature for 10 minutes. 14 μl of PDE (Sigma; 2Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/μl)is then added, followed by 50 μl of 5′-nucleotidase (Sigma; 100 Unitsdissolved in 10 ml of 10 mM Tris-HCl containing 0.5 mM Mg(CH₃COO)₂, pH7.0; stock concentration: 10 Units/ml). The samples are then incubatedfor 10 minutes at 30 C. 50 μl of adenosine 3′,5′-cyclic monophosphate(cAMP) (20 mM in water at pH 7.0) is added, the samples incubated for 1hour at 30 C. and then vortexed. 200 μl of trichloroacetic acid (TCA)(55% in water) is added to a 200 μl sample aliquot, which is thenvortexed and centrifuged for 10 minutes. 80 μl of the resultingsupernatants of each sample is transferred to a 96-well plate, with 2wells each containing 80 μl of each sample. 80 μl of ammonium molybdate(1.1% in 1.1N H₂SO₄) is then added to all the wells, and the OD of eachwere determined at 730 nm, with the values later subtracted to the finalOD reading. 16 μl of reducing agent (6 g sodium bisulfite, 0.6 g sodiumsulfite and 125 mg of 1-amino-2-naphtol-4-sulfonic acid in 50 ml ofwater) is then added to one of each sample duplicate and 16 μl of wateris added to the other duplicate. After sitting for 1 hour at roomtemperature, the OD of each well is determined at 730 nm. The percentinhibition of calmodulin activity is then calculated for each sample,using as 0% inhibition a control sample containing all reagents withoutany test samples and as 100% inhibition a control sample containing testsamples and all reagents except calmodulin. In addition, the percentinhibition of phosphodiesterase activity was determined by following asimilar protocol as the CaMPDE assay described above, except not addingcalmodulin to the sample mixture and calculating the percent inhibitionby using as 0% inhibition a control reagent without any test samples andas 100% inhibition a control sample containing test samples and allreagents except cAMP.

[0234] The following examples are provided to illustrate but not limitthe present invention. The following abreviations have the correspondingmeanings:

[0235] MBHA: 4-methylbenzhydrylamine;

[0236] DMF: N,N-dimethylforamide;

[0237] HOBt: 1-hydroxybenzotriazole;

[0238] DMSO: dimethylsulfoxide;

[0239] Boc: tert-butoxycarbonyl;

[0240] FMOC: 9-fluorenyl-methoxycarbonyl;

[0241] DMAP: 4-dimethylamino-pyridine;

[0242] DIC: N,N′-diisopropylcarbodiimide;

[0243] TFA: trifluoroacetic acid;

[0244] DIEA: N,N-diisopropylethylamine;

[0245] DCM: dichloromethane;

[0246] TMOF: trimethylorthoformate;

[0247] HATU azabenzotriazolyl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate;

[0248] CDI: carbonyldiimidazole

[0249] NMP: N-methylpyrrolidinone

[0250] DMA: N,N-dimethyl acetamide

[0251] RT: room temperature

[0252] IPA: isopropyl alcohol

[0253] MeOH: methanol

[0254] MeOEtOH: 2-methoxyethanol

[0255] DCE: 1,2-dichloroethane

[0256] THF: tetrahydrofuran

[0257] ACN acetonitrile

[0258] Wang resin: p-benzyloxybenzyl alcohol-polystyrene

[0259] Br-Wang resin: p-benzyloxybenzyl bromide-polystyrene

[0260] PP: polypropylene

[0261] PPh3Br2: triphenylphosphine dibromide

[0262] DMAP: 4-dimethylamino-pyridine

[0263] KOtBu: potassium tert-butoxide

[0264] NaOMe: sodium methoxide

[0265] BtCH2CN: 1-(cyanomethyl)benzotriazole

[0266] DBU: 1,8-diazabicyclo[5.4.0] undec-7-ene

[0267] Boc: tertbutoxycarbonyl;

[0268] AcOH: acetic acid

[0269] HPLC/MS: high performance liquid chromatography—massspectrometry;

[0270] FIA/MS: flow injection analysis—mass spectrometry

[0271] ELSD: evaporative light scattering detector

[0272] THB: Todd Hewitt Broth

[0273] OD: optical density

EXAMPLE 1 Synthesis of a Combinatorial Library of 2-amino BenzoxazoleDerivatives (Where Z is Formula A)

[0274] Step 1. Preparation of SASRIN Aldehyde Resin

[0275] Five 2L bottles were run in parallel to prepare 1 kg of SASRINaldehyde resin. The following description is for one of the fiveidentical reactions.

[0276] A 2L Pyrex media bottle was charged with 200 g Merrifield resin(100-200 mesh, 1.46 mmol/g). DMF (700 mL) was added and the bottle wasshaken by hand to distribute the solvent within the swollen resin. A 1LPyrex media bottle was charged with 4-hydroxy-2-methoxybenzaldehyde (140g, 0.92 mol) and the aldehyde was dissolved in DMF (600 mL). Thealdehyde solution was cooled to 0° C. (ice bath) and potassiumtert-butoxide (98 g, 0.88 mol) was added in two equal portions waitingabout 5 min. between additions. The bottle was removed from the ice bathand shaken periodically to help dissolve the potassium tert-butoxide.After the second portion of potassium tert-butoxide was added, thebottle is allowed to warm to 25° C. After 30 min. at 25° C., thepotassium tert-butoxide dissolved, giving the solution a dark ambercolor.

[0277] The phenoxide solution was added to the swollen resin in fourportions, shaking between portions. The 2L bottles were clampedhorizontally in an orbital shaker oven and allowed to shake at 25° C.for 30 min. The temperature was then increased to 50° C. and thereaction shaken for 14 h. After cooling, the resin slurry was pouredinto a 10″×12″ 3-sided porous polypropylene packet (tea bag) sitting ina 2L beaker. After the solvent mixture had drained from the resin, thefourth side of the tea bag was sealed and the tea bags were washed inwide-mouth HDPE Nalgene bottles as follows: 2×DMF, 4×DMF/H₂O (4:1),4×DMF, 4×MeOH. The tea bags were allowed to air dry in a fume hood. From200 g of starting Merrifield resin, 238 g of SASRIN aldehyde resin wasobtained with a loading of 1.2 mmol/g.

[0278] Step 2. Reductive Amination of SASRIN Aldehyde Resin with PrimaryAmines (Step 1 of FIG. 1)

[0279] SASRIN aldehyde resin was swollen in 1% AcOH/DMF (by volume). Theamine (0.15M) was added and the bottle(s) placed on a shaker for 30 min.NaBH₃CN (2 eq to amine, 0.3M) was added, and the reaction bottles placedon a shaker at room temperature for 18 h. The resin was washed asfollows: DMF (4×), MeOH (4×) and then allowed to air dry. For the aminesthat were hydrochloride salts, 1 eq of DIEA was added. The amines addedwere as follows:

[0280] CYCLOPROPYLAMINE

[0281] CYCLOPENTYLAMINE

[0282] CYCLOHEXYLAMINE

[0283] AMINOMETHYLCYCLOHEXANE

[0284] L-LEUCINE

[0285] 1-(2-AMINOETHYL)PYRROLIDINE

[0286] 1-(3-AMINOPROPYL)-2-PYRROLIDINONE

[0287] 1-(1-NAPHTHYL)ETHYLAMINE

[0288] 1-NAPHTHALENEMETHYLAMINE

[0289] CYCLOHEPTYLAMINE

[0290] TETRAHYDROFURFURYLAMINE

[0291] 2-THIOPHENEMETHYLAMINE

[0292] 3,4-METHYLENEDIOXYBENZYLAMINE

[0293] 4-AMINO-2,2,6,6-TETRAMETHYLPIPERIDINE

[0294] 4-(2-AMINOETHYL)MORPHOLINE

[0295] N-(3-AMINOPROPYL)MORPHOLINE

[0296] 2-(2-AMINOETHYL)PYRIDINE

[0297] 3-(AMINOMETHYL)PYRIDINE

[0298] ETHYL 4-AMINO-1-PIPERIDINECARBOXYLATE

[0299] 4-AMINO-1-BENZYLPIPERIDINE

[0300] 1-(2-AMINOETHYL)PIPERIDINE

[0301] P-ANISIDINE

[0302] 1,3-DIMETHYLBUTYLAMINE

[0303] 1-METHYL-3-PHENYLPROPYLAMINE

[0304] 2-AMINO-5-DIETHYLAMINOPENTANE

[0305] BENZYLAMINE

[0306] 2-FLUOROBENZYLAMINE

[0307] 2-CHLOROBENZYLAMINE

[0308] 3-FLUOROBENZYLAMINE

[0309] 3,4-DICHLOROBENZYLAMINE

[0310] 3-METHOXYBENZYLAMINE

[0311] 3,4-DIMETHOXYBENZYLAMINE

[0312] 3-(TRIFLUOROMETHYL)BENZYLAMINE

[0313] 4-FLUOROBENZYLAMINE

[0314] 4-METHYLBENZYLAMINE

[0315] N,N-DIETHYLETHYLENEDIAMINE

[0316] 2-METHOXYETHYLAMINE

[0317] 2-(3,4-DIMETHOXYPHENYL)ETHYLAMINE

[0318] 2-(4-CHLOROPHENYL)ETHYLAMINE

[0319] 2-(4-METHOXYPHENYL)ETHYLAMINE

[0320] PROPARGYLAMINE

[0321] ALLYLAMINE

[0322] N,N-DIMETHYL-1,3-PROPANEDIAMINE

[0323] N,N-DIETHYL-1,3-PROPANEDIAMINE

[0324] 1-(3-AMINOPROPYL)IMIDAZOLE

[0325] 2-(TRIFLUOROMETHYL)BENZYLAMINE

[0326] ETHYL 4-AMINOBUTYRATE HYDROCHLORIDE

[0327] 4-TERT-BUTYLCYCLOHEXYLAMINE

[0328] 1-(3-AMINOPROPYL)PYRROLIDINE

[0329] 2-BROMOBENZYLAMINE

[0330] 2,4-DIMETHYLBENZYLAMINE

[0331] N-(2-AMINOETHYL)-N-ETHYL-M-TOLUIDINE

[0332] 2-ETHOXYETHYLAMINE

[0333] 3—CHLOROBENZYLAMINE

[0334] 3-(METHYLTHIO)PROPYLAMINE

[0335] (R)-(−)-1-CYCLOHEXYLETHYLAMINE

[0336] THIOPHENE-2-ETHYLAMINE

[0337] 3,5-DIMETHOXYBENZYLAMINE

[0338] 2,4-DICHLOROPHENETHYLAMINE

[0339] 4-(TRIFLUOROMETHOXY)BENZYLAMINE

[0340] L-PHENYLALANINE

[0341] L-ALANINE

[0342] 2-FLUOROPHENETHYLAMINE

[0343] 2-(4-FLUOROPHENYL)ETHYLAMINE

[0344] N-(3-AMINOPROPYL)-N-METHYLANILINE

[0345] L-ARGININE

[0346] Step 3. Coupling of Thiomethylbenzoxazole Cores to Resin BoundSecondary Amines (Step 2 of FIG. 1).

[0347] (a) Boc-Deprotection for Boc-Arg (Tos)-mBHA containing bags (seestarting material shown in FIG. 2): Bags were rinsed with DCM, treatedwith a solution of 55% TFA/DCM for 30 minutes, then washed as follows:DCM, IPA (2×), DCM (2×), MeOH, and then air dried. Just prior toacylation did neutralization as follows: DCM, 5% DIEA/DCM, DCM.

[0348] (b) Acylation of all bags was carried out in two batches, eachdone in a 20L Nalgene container, with both Sasrin and mBHA resinsreacted together. For example, a batch of 364 bags (0.66 mol) was placedin the 20L Nalgene bottle, a solution of DCM/DMF (ratio 2:1, 9.5L) wasadded followed by 5-carboxy-2-(methylthio)-1,3-benzoxazole (0.2M, 1.97mol, 410.8 g), 4-dimethylaminopyridine (DMAP, 1.31 mol, 160.09 g), and1,3-diisopropylcarbodiimide (DIC, 1.97 mol, 308 ml). The bottle wasshaken, then vented one time. The bottle was then shaken for 18 h atroom temperature. The resin was washed as follows: DMF (6×), MeOH (4×).The bags were then air dried.

[0349] Step 4. Displacement of S-Me by Symmetrical Diamines (Step 3 ofFIG. 1).

[0350] Eight diamines were used:

[0351] PIPERAZINE

[0352] 4,4′-BIPIPERIDINE DIHYDROCHLORIDE

[0353] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE

[0354] HOMOPIPERAZINE

[0355] 1,4-DIAMINOBUTANE

[0356] N,N′-DIETHYL-1,3-PROPANEDIAMINE

[0357] 1,3-DI-4-PIPERIDYLPROPANE

[0358] 1,8-DIAMINO-3,6-DIOXAOCTANE

[0359] The reactions were run in wide-mouthed glass containers rangingfrom 1L to 5L in size. The excess ranged from 18 to 50 fold, dependingon the amount of solvent necessary to adequately cover the bags. Bagswere added to the appropriate container, anhydrous DMSO was added, andthen the diamine (0.6M). Containers were placed in an oven shaker andheated at 75° C. for 90 h. The containers were then removed from theoven and allowed to cool.

[0360] One DMF wash was performed per container, then the bags werecombined in a 20L Nalgene container for the remaining washes: DMF (5×),MeOH (4×), then bags were placed in a fume hood to air dry.

[0361] Step 5. Derivatization of the Substituted Aminobenzoxazole (Step4 of FIG. 1).

[0362] Acylation (X═C(O)): For 45 μmol aminobenzoxazole resin per wellof a 96-well microtiter plate, 700 μL RCO₂H/DIEA/DMAP/DCM-DMF (0.5M,0.35 mmol RCO₂H; 1.1M, 0.77 mmol DIEA; 0.16M, 0.112 mmol DMAP; 2:1DCM-DMF) and 700 μL HBTU/DMF (0.5M, 0.35mmol) were added to each well.The carboxylic acids (RCO₂H) used were as follows:

[0363] CYCLOPROPANECARBOXYLIC ACID

[0364] 1-METHYLCYCLOPROPANE-1-CARBOXYLIC ACID

[0365] 1-METHYL-1-CYCLOHEXANECARBOXYLIC ACID

[0366] TRANS-1,2-CYCLOHEXANEDICARBOXYLIC ACID

[0367] (−)-MENTHOXYACETIC ACID

[0368] 1,1-CYCLOHEXANEDIACETIC ACID

[0369] BENZOIC ACID

[0370] N-PHENYLANTHRANILIC ACID

[0371] FLUFENAMIC ACID

[0372] 2,4-DIMETHYLBENZOIC ACID

[0373] 3-BENZOYLBENZOIC ACID

[0374] 2-PROPYLPENTANOIC ACID

[0375] 2-ETHYLHEXANOIC ACID

[0376] TRANS-2-PENTENOIC ACID

[0377] TERT-BUTYLACETIC ACID

[0378] 2-KETOBUTYRIC ACID

[0379] 2-ETHYL-2-HYDROXYBUTYRIC ACID

[0380] METHOXYACETIC ACID

[0381] 2-(TRIFLUOROMETHYL)PHENYLACETIC ACID

[0382] 4-(TRIFLUOROMETHYL)PHENYLACETIC ACID

[0383] 5—CHLOROVALERIC ACID

[0384] 3-FUROIC ACID

[0385] N-ACETYL-DL-TRYPTOPHAN

[0386] 3-INDOLEPROPIONIC ACID

[0387] 3,4-DIFLUOROPHENYLACETIC ACID

[0388] 3-(PHENYLSULFONYL)PROPIONIC ACID

[0389] 2,4-DIFLUOROBENZOIC ACID

[0390] 3-CYCLOHEXENECARBOXYLIC ACID

[0391] 2-BENZYLOXYPHENYLACETIC ACID

[0392] N-ACETYL-L-PROLINE

[0393] 1-ACETYLPIPERIDINE-4-CARBOXYLIC ACID

[0394] 5-CHLOROTHIOPHENE-2-CARBOXYLIC ACID

[0395] 2-(2-METHOXYETHOXY)ACETIC ACID

[0396] BENZO[B]THIOPHENE-3-ACETIC ACID

[0397] METHANESULFONYLACETIC ACID

[0398] 5-HEXYNOIC ACID

[0399] 3-FLUORO-2-METHYL-BENZOIC ACID

[0400] 2-METHYL-3-FUROIC ACID

[0401] 6-HEPTYNOIC ACID

[0402] 5-METHYLISOXAZOLE-4-CARBOXYLIC ACID

[0403] The Plates were capped, vortexed, and placed on a shaker at roomtemperature for 48 h. The resin was washed by DMF (7×), MeOH (6×), anddried.

[0404] Sulfonylation (X═SO₂) For 45 μmol of aminobenzoxazole resin ineach well of a 96-well microtiter plate, 1 mL RSO₂Cl/THF-ACN /NMM/NMI(0.3M, 0.3 mmol RSO₂Cl; 20% THF-ACN (by volume); 0.6M, 0.6 mmol NMM;0.1M, 0.1 mmol NMI) was added to each well. The sulfonyl chlorides(RSO₂Cl) used were as follows:

[0405] 1 -NAPHTHALENESULFONYL CHLORIDE

[0406] 2-NAPHTHALENESULFONYL CHLORIDE

[0407] 2-ACETAMIDO-4-METHYL-5-THIAZOLESULFONYL CHLORIDE

[0408] 2-THIOPHENESULFONYL CHLORIDE

[0409] 8-QUINOLINESULFONYL CHLORIDE

[0410] 2-MESITYLENESULFONYL CHLORIDE

[0411] 3-NITROBENZENESULFONYL CHLORIDE

[0412] 4-BROMOBENZENESULFONYL CHLORIDE

[0413] 4-FLUOROBENZENESULFONYL CHLORIDE

[0414] 4-CHLOROBENZENESULFONYL CHLORIDE

[0415] 4-ACETAMIDOBENZENESULFONYL CHLORIDE

[0416] 4-NITROBENZENESULFONYL CHLORIDE

[0417] 4-TERT-BUTYLBENZENESULFONYL CHLORIDE

[0418] PENTAMETHYLBENZENESULFONYL CHLORIDE

[0419] 2,3,5,6-TETRAMETHYLBENZENESULFONYL CHLORIDE

[0420] P-XYLENE-2-SULFONYL CHLORIDE

[0421] 3,4-DICHLOROBENZENESULFONYL CHLORIDE

[0422] 3-CHLORO-4-FLUOROBENZENESULPHONYL CHLORIDE

[0423] 4-ETHYLBENZENESULFONYL CHLORIDE

[0424] 4-N-PROPYLBENZENESULFONYL CHLORIDE

[0425] 4-N-AMYLBENZENESULFONYL CHLORIDE

[0426] 4-ISOPROPYLBENZENESULPHONYL CHLORIDE

[0427] 3-FLUOROBENZENESULPHONYL CHLORIDE

[0428] 4-(TRIFLUOROMETHYL)BENZENESULFONYL CHLORIDE

[0429] 2-CHLOROBENZENESULFONYL CHLORIDE

[0430] 5-CHLOROTHIOPHENE-2-SULFONYL CHLORIDE

[0431] 3-CHLOROBENZENESULFONYL CHLORIDE

[0432] 3,5-DICHLOROBENZENESULFONYL CHLORIDE

[0433] M-TOLUENESULFONYL CHLORIDE

[0434] 2-CHLORO-6-METHYLBENZENESULFONYL CHLORIDE

[0435] 2-BROMOBENZENESULFONYL CHLORIDE

[0436] 2,4-DICHLOROBENZENESULFONYL CHLORIDE

[0437] 1-METHYLIMIDAZOLE-4-SULPHONYL CHLORIDE

[0438] 2-(METHOXYCARBONYL)THIOPHENE-3-SULPHONYL CHLORIDE

[0439] P-STYRENESULFONYL CHLORIDE

[0440] 3,4-DIFLUOROBENZENESULPHONYL CHLORIDE

[0441] 4-PENTYLBENZENE-1-SULFONYL CHLORIDE

[0442] 4-N-BUTYLBENZENESULFONYL CHLORIDE

[0443] 3-CHLORO-4-METHYLBENZENESULPHONYL CHLORIDE

[0444] 2-METHYLSULFONYLBENZENESULFONYL CHLORIDE

[0445] Plates were capped, vortexed, and placed on a shaker at roomtemperature for 48 h. The resin was washed by ACN (6×), MeOH (6×), andthen air dried.

[0446] Step 6. Cleavage from Linker and Extraction (Step 5 of FIG. 5).

[0447] Because three different types of resins were used, threedifferent cleavage procedure resulted.

[0448] (a) Sasrin resin, no side-chain protection in the R₁ position: Tothe dry microtiter plates containing the aminobenzoxazole resins wasadded 0.5 mL of 10% TFA/DCM to each well containing resin. Plates werecapped and placed on a shaker at room temperature for 3 h. Plates weretransferred to a GENEVAC to remove the volatile TFA/DCM solution. Theplates were extracted with acetic acid and the extractions werelyophilized. The final substituted-aminobenzoxazole products were thenanalyzed by FIA/MS and HPLC/ELSD.

[0449] (b) Sasrin resin, tert-Butyl ester protection of the R1side-chain: To the dry microtiter plates containing the aminobenzoxazoleresins was added 0.5 mL of 20% TFA/DCM to each well containing resin.Plates were capped and placed on a shaker at room temperature for 3 h.Plates were transferred to a GENEVAC (Valley College, N.Y.) to removethe volatile TFA/DCM solution. The plates were extracted with aceticacid and the extractions were lyophilized. The finalsubstituted-aminobenzoxazole products were then analyzed by FIA/MS andHPLC/ELSD.

[0450] (c) MBHA resin: The dry microtiter plates containing theaminobenzoxazole resin were placed in an HF chamber and sealed. Thechamber was flushed with nitrogen for 1 h. Gaseous HF was then added tothe chamber for 30 minutes. The chamber was isolated and allowed tostand at room temperature for 2 h. To remove HF, the chamber was flushedwith nitrogen for 2.5 h. The plates were removed from the HF chamber andplaced in a dessicator under vacuum overnight. The plates were extractedwith acetic acid and the extractions were lyophilized. The finalsubstituted-aminobenzoxazole products were then analyzed by FIA/MS andHPLC/ELSD.

EXAMPLE 2 Synthesis of a Combinatorial Library of 2-amino BenzoxazoleDerivatives (Where Z is Formula B)

[0451] Step 1. Reductive Amination of SASRIN Aldehyde Resin with PrimaryAmines

[0452] 2.5 g tea bags containing SASRIN aldehyde resin were swollen in1% AcOH/DMF (by volume) . An amine (0.15M) was added and the bottle(s)placed on a shaker for 30 min. (see amines listed in step 1 of Example1). NaBH₃CN (2 eq to amine, 0.3M) was added and the reaction bottlesplaced on a shaker at room temperature for 18 hours, with the bottlesneed to be vented after the first 30 min. to prevent pressure build updue to the release of H₂(g). The resin was washed as follows: DMF (4×),MeOH (4×) and then allowed to air dry. For the amines that werehydrochloride salts, 1 eq of DIEA was added.

[0453] Step 2. Coupling of Thiomethylbenzoxazole Cores to Resin BoundSecondary Amine

[0454] Acylation of all bags was carried out in two batches, each donein a 20L Nalgene container. For example, a batch of 256 bags was placedin the 20L Nalgene bottle, a solution of DCM/DMF (ratio 2:1, 7L) wasadded followed by 5-carboxy-2-(methylthio)-1,3-benzoxazole (0.2M, 1.4mol, 293 g), 4-dimethylaminopyridine (DMAP, 0.91 mol, 111 g), and1,3-diisopropylcarbodiimide (DIC, 1.4 mol, 220 ml). The container wasshaken, vented and placed on a shaker for 18 h at room temperature. Theresin was washed as follows: DMF (6×), MeOH (4×). The bags were dried.

[0455] Step 3. Displacement of S-Me by Amino Alcohols

[0456] 3 amino alcohols used: L-pyrrolinol, 3-piperidine methanol, andN-(2-hydroxyethyl)piperazine. The reactions were run in wide-mouthedglass containers ranging from 4L to 6L in size. Bags were added to theappropriate container, N,N-dimethylacetamide was added followed bytetramethylguanidine (TMG) and the amino alcohol (0.6M). Containers wereplaced in an oven shaker and heated at 73° C. for 64 h. The containerswere then removed from the oven and allowed to cool. One DMF wash wasperformed per container, then the bags were combined in a 20L Nalgenecontainer for the remaining washes: DMF (5×), MeOH (4×). The bags wereplaced in a fume hood to air dry.

[0457] Step 4. Bromination of the Primary Alcohols

[0458] Bromination was carried out in four batches. The followingdescription is for one of the four identical batches. A 8 L glass vesselwash charged with 7 L of DCM, Ph₃P Br₂ (840 g, 2.0 mol) and Et₃N (840mL, 6.0 mol). After mixing the solution to dissolve the reagent, 130 teabags were added and the vessel placed on a shaker for 16 h. The bagswere washed with DCM (×2), MeOH (×1), DMF (×4), and MeOH (×3). Afterdrying the resin, the intermediates were analyzed by HPLC-MS.

[0459] Step 5. Displacement of Bromide with Primary and Secondary Amines

[0460] After resin distribution into 96 well mircotiter plates, eachamine was dissolved in a solution of 0.3M TMG in DMF to make a solutionthat was 0.6M in amine. The amines used were as follows:

[0461] Nipecotamide

[0462] L-Prolinamide

[0463] Pyrrolidine

[0464] Piperidine

[0465] 1-methylpiperazine

[0466] Ethanol amine

[0467] Morpholine

[0468] 2-piperidinemethanol

[0469] N-methylbenzylamine

[0470] Ethyl isonipecotate

[0471] 1-phenylpiperazine

[0472] 1-(2-pyrimidyl)-piperazine

[0473] N-methylcyclohexylamine

[0474] N-methylisobutylamine

[0475] Thiomorpholine

[0476] R-(−)-1-cyclohexylethylamine

[0477] 1,2,3,4,-tetrahydroisoquinoline

[0478] N-ethylbenzylamine

[0479] N,N,N′-triethylethylenediamine

[0480] 1-benzylpiperazine

[0481] Neopentylamine

[0482] Aminomethylcyclohexane

[0483] Homopiperazine

[0484] Decahydroquinoline

[0485] Hexamethyleneimine

[0486] Ethyl nipecotate

[0487] N-methyl-N-propylamine

[0488] N,N,N′-trimethyl-1,3-propanediamine

[0489] 4-hydroxypiperidine

[0490] 2,6-dimethylpiprazine

[0491] 1-methylhomopiperazine

[0492] 2-methylpiperidine

[0493] 3,5-dimethylpiperidine

[0494] 3-(dimethylamino)pyrrolidine

[0495] 3-(tert-butoxycarbonylamino)pyrrolidine

[0496] N-methylallylamine

[0497] N-methyl-Beta-alaninenitrile

[0498] Di-(2-picolyl)amine

[0499] N-heptylmethylamine

[0500] 2-(ethylamino)ethanol

[0501] N-ethyl-N-butylamine

[0502] N-ethylpiperazine

[0503] 2,6-dimethylmorpholine

[0504] N-sec-butyl-N-propylamine

[0505] N-(N-butyl)-N-propylamine

[0506] 3-(ethylamino)-propionitrile

[0507] Using robotic delivery, 1 mL of the amine solution was added tothe wells of the microtiter plates containing the bromide resins. Theplates were vortexed and were placed in a shaker oven at 50° C. for 64h. After cooling to room temperature, the resin was robotically washedusing DMF (×8) and MeOH (×6).

[0508] Step 6. Cleavage from Linker and Extraction

[0509] To dry microtiter plates containing the aminobenzoxazole resinswas added 0.5 mL of 10% TFA/DCM to each well. The plates were capped andplaced on a shaker at room temperature for 3 h. The plates weretransferred to a GENEVAC to remove the volatile TFA/DCM solution. Theplates were extracted with ACOH and the extract frozen and lyophilizedto afford the products as yellow oils. All of the final products wereanaylzed by HPLC/MS using ELSD detection to determine purity.

EXAMPLE 3 Anti-microbial Screen

[0510] Streptococcus pyogenes (ATCC# 97-03 14289) are grown in ToddHewitt Broth (THB) (Difco Laboratories #0492-17-6) overnight until theyreach an optical density of (OD=0.636@ 570 nm) by reading 0.1 ml in a 96well microtiter plate in a Molecular Devices Thermomax. This preparationis kept frozen as stocks in 30% v/v glycerol in 1.5 ml aliquots at −70°C. until use. Prior to experiments, 1.5 ml aliquots are thawed anddiluted into 50 ml THB. 200 ul of this dilution is added to 92 wells ofmicrotiter plate. To three wells THB (200 ul) is added to serve as ablank and a sterility control. Test compounds in DMSO and appropriateconcentrations of DMSO are added to Growth/Solvent Controls at 0 time.Plates are read at 0 time at 570 nm in the Molecular Devices platereader to obtain compounds correction factors for insoluble or coloredcompounds. Plates are read again at 4 hrs.

[0511] Percent inhibition is calculated with the following formulae:

Color correct=(O.D. 0 hr−Blank 0 hr)−(Solvent Control 0 hr−Blank 0 hr) %Inhibition=

[0512]${\% \quad {Inhibition}} = {100 - \frac{{{O.D.\quad {test}}\quad {compound}\quad 4\quad {hr}} - {{Blank}\quad 4\quad {hr}} - {{color}\quad {correct}}}{{{{O.D.\quad {growth}}/{solvent}}\quad {control}\quad 4\quad {hr}} - {{Blank}\quad 4\quad {hr}}}}$

EXAMPLE 4 Melanocortin Receptor Assay

[0513] This example describes methods for assaying binding to MCreceptors.

[0514] All cell culture media and reagents are obtained from GibcoBRL(Gaithersburg Md.), except for COSMIC CALF SERUM (HyClone; Logan Utah).HEK 293 cell lines are transfected with the human MC receptors hMCR-1,hMCR-3, and hMCR-4 (Gantz et al., Biochem. Biophys. Res. Comm.200:1214-1220 (1994); Gantz et al., J. Biol. Chem. 268:8246-8250 (1993);Gantz et al. J. Biol. Chem. 268:15174-15179 (1993); Haskell-Leuvano etal., Biochem. Biophys. Res. Comm. 204:1137-1142 (1994); each of which isincorporated herein by reference). Vectors for construction of an hMCR-5expressing cell line are obtained, and a line of HEK 293 cellsexpressing hMCR-5 is constructed (Gantz, supra, 1994). hMCR-5 has beendescribed previously (Franberg et al., Biochem. Biophys. Res. Commun.236:489-492 (1997); Chowdhary et al., Cytogenet. Cell Genet. 68:1-2(1995); Chowdhary et al., Cytogenet. Cell Genet. 68:79-81 (1995), eachof which is incorporated herein by reference). HEK 293 cells aremaintained in DMEM, 25 mM HEPES, 2 mM glutamine, non-essential aminoacids, vitamins, sodium pyruvate, 10% COSMIC CALF SERUM, 100 units/mlpenicillin, 100 μg/ml streptomycin and 0.2 mg/ml G418 to maintainselection.

[0515] Before assaying, cells are washed once with phosphate bufferedsaline (“PBS”; without Ca²⁺ and Mg²⁺), and stripped from the flasksusing 0.25% trypsin and 0.5 mM EDTA. Cells are suspended in PBS, 10%COSMIC CALF SERUM and 1 mM CaCl₂. Cell suspensions are prepared at adensity of 2'10⁴ cells/ml for HEK 293 cells expressing hMCR-3, hMCR-4 orhMCR-5, and 1×10⁵ cells/ml for HEK 293 cells expressing hMCR-1.Suspensions are placed in a water bath and allowed to warm to 37 C. for1 hr.

[0516] Binding assays are performed in a total volume of 250 μl for HEK293 cells. Control and test compounds are dissolved in distilled water.¹²⁵I-HP 467 (50,000 dpm) (2000 Ci/mmol) (custom labeled by Amersham;Arlington Heights Ill.) is prepared in 50 mM Tris, pH 7.4, 2 mg/ml BSA,10 mM CaCl₂, 5 mM MgCl₂, 2 mM EDTA and added to each tube. To each tubeis added 4×10³ HEK 293 cells expressing hMCR-3, hMCR-4 or hMCR-5, or2×10⁴ cells expressing hMCR-1. Assays are incubated for 2.5 hr at 37 C.

[0517] GF/B filter plates are prepared by soaking for at least one hourin 5 mg/ml BSA and 10 mM CaCl₂. Assays are filtered using a Brandel96-well cell harvester (Brandel Inc.; Gaithersburg, Md.). The filtersare washed four times with cold 50 mM Tris, pH 7.4, and the filterplates dehydrated for 2 hr and 35 pl of MICROSCINT is added to eachwell. Filter plates are counted using a Packard Topcount (PackardInstrument Co.) and data analyzed using GraphPad PRISM v2.0 (GraphPadSoftware Inc.; San Diego Calif.) and Microsoft EXCEL v5.0a (MicrosoftCorp.; Redmond Wash.).

[0518] To assay 2-aminobenzoxazole derivative compounds, binding assaysare performed in duplicate in a 96 well format. HP 467 is prepared in 50mM Tris, pH 7.4, and ¹²⁵I-HP 467 is diluted to give 100,000 dpm per 50μl. A 2-aminobenzoxazole derivative compound, synthesized as describedin Examples 1 to 3, is added to the well in 25 μl aliquots. A 25 μlaliquot of ¹²⁵I-HP 467 is added to each well. A 0.2 ml aliquot ofsuspended cells is added to each well to give the cell numbers indicateabove, and the cells are incubated at 37 C. for 2.5 hr. Cells areharvested on GF/B filter plates as described above and counted.

EXAMPLE 5 Penile Erection Due to Administration of a 2-aminobenzoxazoleDerivative Compound

[0519] Adult male rats are housed 2-3 per cage and are acclimated to thestandard vivarium light cycle (12 hr. light, 12 hr. dark), rat chow andwater for a least a week prior to testing. All experiments are performedbetween 9 a.m. and noon and rats are placed in cylindrical, clearplexiglass chambers during the 60 minute observation period. Mirrors arepositioned below and to the sides of the chambers, to improve viewing.

[0520] Observations begin 10 minutes after an unstraperitoneal injectionof either saline or compound. An observer counts the number of groomingmotions, stretches, yawns and penile erections (spontaneously occurring,not elicited by genital grooming) and records them every 5 minutes, fora total of 60 minutes. The observer is unaware of the treatment andanimals are tested once, with n=6 in each group. Values in the figuresrepresent the group mean and standard error of the mean. HP 228 can beused as a positive control for penile erections. Significant differencesbetween groups are determined by an overall analysis of variance and theStudent Neunmann-Keuls post hoc test can be used to identify individualdifferences between groups (p 0.05).

[0521] All references cited herein are fully incorporated by reference.

[0522] Although the invention has been described with reference to theexamples provided above, it should be understood that variousmodifications can be made by those skilled in the art without departingfrom the invention. Accordingly, the invention is set out in thefollowing claims.

We claim:
 1. A single compound of the structure:

wherein R₁ and R₄, and one of R₂ and R₃, are independently selected fromthe group consisting of a hydrogen atom, halo, hydroxy, protectedhydroxy, cyano, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl,C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂substituted alkynyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁to C₁₂ acyloxy, C₁ to C₁₂ acyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substitutedcycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C₇ toC₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, phenyl,substituted phenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene, carboxy,protected carboxy, hydroxymethyl, protected hydroxymethyl, protectedamino, protected (monosubstituted)amino, (disubstituted)amino, C₁ to C₁₀alkyl protected amino, C₁ to C₁₀ alkyl protected (monosubstituted)amino,C₁ to C₁₀ alkyl(disubstituted)amino, C₁ to C₁₀ substituted alkylamino,C₁ to C₁₀ substituted alkyl protected (monosubstituted)amino, C₁ to C₁₀substituted alkyl(disubstituted)amino, carboxamide, C₁ to C₁₀ alkylthio,C₁ to C₁₀ substituted alkylthio, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀substituted alkylsulfonyl, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀substituted alkylsulfoxide, phenylthio, substituted phenylthio,phenylsulfoxide, substituted phenylsulfoxide, phenylsulfonyl,substituted phenylsulfonyl and the group consisting of (i) the formula—C(O)NR¹¹R¹², (ii) the formula —SR¹¹, (iii) the formula —OR¹¹ and (iv)the formula —C(O)OR¹¹, wherein R¹¹and R¹² are, independently, selectedfrom the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, heteroaryl,substituted heteroaryl, heterocycle and substituted heterocycle; theother of R₂ and R₃ is selected from the group consisting of a hydrogenatom, halo, hydroxy, protected hydroxy, carboxy, thio, C₁ to C₁₂ alkyl,C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ toC₁₂ substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₁ to C₁₂alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyloxy, C₁ to C₁₂ acyl,C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocyclic ring,substituted heterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂substituted heterocycloalkyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, carboxy, protected carboxy, hydroxymethyl, protectedhydroxymethyl, protected amino, protected (monosubstituted)amino,(disubstituted)amino, C₁ to C₁₀ alkyl protected amino, C₁ to C₁₀ alkylprotected (monosubstituted)amino, C₁ to C₁₀ alkyl(disubstituted)amino,C₁ to C₁₀ substituted alkyl protected amino, C₁ to C₁₀ substituted alkylprotected (monosubstituted)amino, C₁ to C₁₀ substitutedalkyl(disubstituted)amino, carboxamide, C₁ to C₁₀ alkylthio, C₁ to C₁₀substituted alkylthio, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substitutedalkylsulfonyl, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ substitutedalkylsulfoxide, phenylthio, substituted phenylthio, phenylsulfoxide,substituted phenylsulfoxide, phenylsulfonyl, substituted phenylsulfonyland the group consisting of (i) the formula —C(O)NR¹¹R¹², (ii) theformula —SR¹¹, (iii) the formula —OR¹¹, (iv) the formula —C(O)OR¹¹ and(v) the formula S(O)₂NR¹¹R¹², wherein R¹¹ and R¹² are, independently,selected from the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl,C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substitutedalkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, heteroaryl,substituted heteroaryl, heterocycle and substituted heterocycle; Z isthe structure A:

 or the structure B:

 or the structure C:

 wherein, in structure A, Q is the formula ((CH₂)_(n)NH)_(m), where m is0 or 1, n is 1 to 6 and the alkylene portion of Q is directly attachedto the depicted nitrogen atom in structure A; and the dotted linebetween R₆ and R₇ indicates that R₆ and R₇ are optionally directlyattached; wherein, in structure B, the depicted cyclic portion is anunsubstituted or substituted heterocycle that is fully saturated,contains 4 to 7 ring atoms, 1 to 2 nitrogen rings atoms and 0 to 1 otherheteroatoms selected from oxygen and sulfur; wherein, in structure C, Kis absent or present and, if present, is a C₁ to C₁₂ alkylene; R₅ isselected from the group consisting of C₁ to C₁₀ alkylene, C₂ to C₁₀alkenylene, C₂ to C₁₀ alkynylene, C₁ to C₁₀ substituted alkylene, C₂ toC₁₀ substituted alkenylene, C₂ to C₁₀ substituted alkynylene,substituted epimino, C₁ to C₅ substituted alkylene epimino, thio, C₁ toC₁₀ alkylene thio, C₁ to C₁₀ substituted alkylene thio, sulfonyl, C₁ toC₁₀ alkylene sulfonyl, C₁ to C₁₀ substituted alkylene sulfonyl,sulfinyl, C₁ to C₁₀ alkylene sulfinyl, C₁ to C₁₀ substituted alkylenesulfinyl, oxy, C₁ to C₁₀ alkylene oxy, C₁ to C₁₀ substituted alkyleneoxy, C₁ to C₁₀ alkylene dioxy, C₁ to C₁₀ substituted alkylene dioxy, C₁to C₁₀ alkylene trioxy and C₁ to C₁₀ substituted alkylene trioxy; X isabsent or present and, if present, is selected from the group consistingof carbonyl, thiocarbonyl, thioester, sulfonyl and sulfinyl; where R₆and R₇ are not directly attached to each other, they are independentlyselected from the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl,C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ toC₁₂ substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₃ to C₇cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅to C₇ substituted cycloalkenyl, heterocyclic ring, substitutedheterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂ substitutedheterocycloalkyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, hydroxymethyl and protected hydroxymethyl; or where R₆and R₇ are directly attached to each other are, collectively selectedfrom the group consisting of C₁ to C₅ alkylene, C₂ to C₅ alkenylene, C₂to C₅ alkynylene, C₁ to C₅ substituted alkylene, C₂ to C₅ substitutedalkenylene, C₂ to C₅ substituted alkynylene, substituted epimino, C₁ toC₅ substituted alkylene epimino, thio, C₁ to C₅ alkylene thio, C₁ to C₅substituted alkylene thio, sulfonyl, C₁ to C₅ alkylene sulfonyl, C₁ toC₅ substituted alkylene sulfonyl, sulfinyl, C₁ to C₅ alkylene sulfinyl,C₁ to C₅ substituted alkylene sulfinyl, oxy, C₁ to C₅ alkylene oxy, C₁to C₅ substituted alkylene oxy, C₁ to C₅ alkylene dioxy, C₁ to C₅substituted alkylene dioxy, C₁ to C₅ alkylene trioxy and C₁ to C₅substituted alkylene trioxy; and X is absent or present and, if present,is selected from the group consisting of carbonyl, thiocarbonyl,thioester, sulfonyl and sulfinyl; and R₈ and, if present, R₉ areindependently selected from the group consisting of a hydrogen atom, C₁to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂ substitutedalkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocyclic ring,substituted heterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂substituted heterocycloalkyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, protected hydroxymethyl, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, C₁ to C₁₀ alkylamino, C₁ to C₁₀ alkyl protectedamino, C₁ to C₁₀ alkyl (monosubstituted)amino, C₁ to C₁₀ alkyl,protected (monosubstituted)amino, C₁ to C₁₀ alkyl(disubstituted)amino,C₁ to C₁₀ substituted alkylamino, C₁ to C₁₀ substituted alkyl protectedamino, C₁ to C₁₀ substituted alkyl (monosubstituted)amino, C₁ to C₁₀substituted alkyl protected (monosubstituted)amino, C₁ to C₁₀substituted alkyl(disubstituted)amino, carboxamide, protectedcarboxamide, and the group consisting of (i) the formula —C(O)NR¹¹R¹²,(ii) the formula —C(O)R¹¹, (iii) the formula —NR¹¹R¹², (iv) the formula—C(O)OR¹¹, wherein R¹¹ and R¹² are, independently, selected from thegroup consisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, heteroaryl,substituted heteroaryl, heterocycle, substituted heterocycle, C₁ to C₁₂acyl, C₁ to C₁₂ substituted acyl, phenylsulfonyl, substitutedphenylsulfonyl, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substitutedalkylsulfonyl, C₁ to C₁₂ alkylaminocarbonyl, C₁ to C₁₂ substitutedalkylaminocarbonyl, phenylaminocarbonyl, and substitutedphenylaminocarbonyl; or R₈ and R₉, together with the adjoining nitrogendepicted in structure B are, collectively, selected from the groupconsisting of heterocycle and substituted heterocycle; provided that, ifX is carbonyl, R₈ is not alkoxy; and provided that X can only be absentwhere R₆ and R₇ are not directly attached to each other; or a salt ofsaid compound.
 2. The single compound of claim 1, wherein: R₁ and R₄ areindependently selected from the group consisting of a hydrogen atom,halo, C₁ to C₁₂ alkyl and C₁ to C₁₂ substituted alkyl.
 3. The singlecompound of claim 1, wherein: one of R₂ and R₃ is selected from thegroup consisting of a hydrogen atom, halo, C₁ to C₁₂ alkyl and C₁ to C₁₂substituted alkyl; and the other of R₂ and R₃ is selected from the groupconsisting of hydrogen atom, halo, hydroxy, carboxy, thio, carboxamide,the formula —C(O)NR¹¹R¹² and the formula S(O)₂NR¹¹R¹², wherein R¹¹ andR¹² are, independently, selected from the group consisting of a hydrogenatom, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl,C₂ to C₁₂ substituted alkenyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl and C₁ to C₁₂ substitutedheterocycloalkyl.
 4. The single compound of claim 1, wherein R₆ and R₇are not directly attached to each other and are independently selectedfrom the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₃ to C₇ cycloalkyl and C₃ to C₇ substitutedcycloalkyl.
 5. The single compound of claim 1, wherein: R₈ and, ifpresent, R₉ are independently selected from the group consisting of ahydrogen atom, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁to C₁₂ substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₃ to C₇cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅to C₇ substituted cycloalkenyl, heterocyclic ring, substitutedheterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂ substitutedheterocycloalkyl, phenyl, substituted phenyl, cyclic C₂ to C₇ alkylene,substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇ heteroalkylene andsubstituted cyclic C₂ to C₇ heteroalkylene; or R₈ and R₉, together withthe adjoining nitrogen depicted in structure B are, collectively,selected from the group consisting of heterocycle and substitutedheterocycle.
 6. The single compound of claim 1, wherein R₅ is selectedfrom the group consisting of C₁ to C₈ alkylene and C₁ to C₈ substitutedalkylene.
 7. The single compound of claim 1, wherein R₆ and R₇ aredirectly attached to each other and are, collectively, selected from thegroup consisting of C₁ to C₅ alkylene and C₁ to C₅ substituted alkylene.8. The single compound of claim 1, wherein X is absent.
 9. The singlecompound of claim 1, wherein X is selected from the group consisting ofcarbonyl and sulfonyl.
 10. The single compound of claim 1, wherein: R₁and R₄, and one of R₂ and R₃, are independently selected from the groupconsisting of a hydrogen atom, halo, protected hydroxy, cyano, C₁ to C₁₂alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substitutedalkyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₁to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, phenyl, substituted phenyl,(disubstituted)amino, C₁ to C₁₀ alkylthio and C₁ to C₁₀ substitutedalkylthio; the other of R₂ and R₃ is selected from the group consistingof a hydrogen atom, halo, hydroxy, carboxy, thio, carboxamide, theformula —C(O)NR¹¹R¹² and the formula S(O)₂NR¹¹R¹², wherein R¹¹ and R¹²are, independently, selected from the group consisting of a hydrogenatom, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl,C₂ to C₁₂ substituted alkenyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl and C₁ to C₁₂ substitutedheterocycloalkyl; and where R₆ and R₇ are not directly attached to eachother, are independently selected from the group consisting of ahydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂ substituted alkyl, C₃ to C₇cycloalkyl and C₃ to C₇ substituted cycloalkyl; R₈ and, if present, R₉are independently selected from the group consisting of a hydrogen atom,C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₃ to C₇ cycloalkyl,C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇substituted cycloalkenyl, heterocyclic ring, substituted heterocyclicring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ toC₁₂ heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, phenyl,substituted phenyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene and substituted cyclic C₂ toC₇ heteroalkylene; or R₈ and R₉, together with the adjoining nitrogendepicted in structure B are, collectively, selected from the groupconsisting of heterocycle and substituted heterocycle; and R₅ isselected from the group consisting of C₁ to C₈ alkylene and C₁ to C₈substituted alkylene; where R₆ and R₇ are directly attached to eachother, they are, collectively, selected from the group consisting of C₁to C₅ alkylene and C₁ to C₅ substituted alkylene; and X is absent orpresent and, if present, is selected from the group consisting ofcarbonyl and sulfonyl.
 11. The compound of claim 1, wherein Z is thestructure A.
 12. The compound of claim 1, wherein Z is the structure B.13. The compound of claim 11, wherein R₆ and R₇ are directly attached toeach other.
 14. The compound of claim 11, wherein R₆ and R₇ are notdirectly attached to each other.
 15. The compound of claim 11, whereinthe cyclic portion of structure A is selected from the group consistingof 1,4-piperazine and 1,4-homopiperazine.
 16. The compound of claim 1,wherein: R₁ and R₄ are each hydrogen; and one of R₂ and R₃ is hydrogenand the other is the formula —C(O)NR¹¹R¹², wherein one of R¹¹ and R¹² ishydrogen and the other is selected from the group consisting of2-morpholin-4-yl-ethyl, 3-pyrrolidin-1-yl-propyl, allyl, 3-fluorobenzyl,2-piperidin-1-yl-ethyl, 4-morpholino-3-propyl, ethyl-4-butyryl,2-methoxyethyl, benzyl, 4-methylbenzyl, N,N-diethylethylene,N,N-diethyl-1,3-propylene, 3,5-dimethoxybenzyl, 4-fluorophenethyl,4-fluorobenzyl, 2-fluorophenethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-pyridin-2-yl-ethyl, propargyl, 2-pyrrolidin-1-yl-ethyl,2-chlorobenzyl, cyclopropyl, pyridin-3-yl-methyl, 2-thiophenemethyl,3-(methylthio)propyl, cyclohexanemethyl, 2-ethoxyethyl, cyclopentyl,cyclohexyl, 3-chlorobenzyl, 4-methoxyphenethyl, 2-(4-chlorophenyl)ethyl,3-dimethylamino-1-propyl, 3,4-dimethoxybenzyl, 2-bromobenzyl,N-(3-propyl)-N-methylaniline, 2-propionic acid, 2-(3-phenyl)-propionicacid, 2-(4-methyl)-pentanoic acid, (±)-tetrahydrofuryl,3-imidazol-1-yl-propyl, 2-trifluoromethylbenzyl, cycloheptyl,2,4-dichlorophenethyl, 1-(3-propyl)-pyrrolidin-2-one,4-tert-butylcyclohexyl, 2,2,6,6-tetramethyl-piperidin-4-yl,5-diethylamino-2-pentyl, 1,3-dimethylbutyl, 2,4-dimethylbenzyl,thiophene-2-ethyl, 4-methoxyphenyl, 4-piperidino-1-carboxylic acid ethylester, 3-methoxybenzyl, N-1-ethyl-N-1-m-tolyl-2-ethyl,1-benzyl-piperidin-4-yl, 1-methyl-3-phenylpropyl, 2-fluorobenzyl,3-(trifluoromethyl)benzyl, piperonyl, 1-naphthalenemethyl,3,4-dichlorobenzyl, (R)-(−)-1-cyclohexylethyl,(+/−)-1-(1-naphthyl)ethyl, 4-(trifluoromethoxy)benzyl and5-guanidinopentanoic acid-2-yl.
 17. The single compound of claim 16,wherein: Z is the structure A or the structure C, wherein: X is carbonyland the combination of X—R₈ is selected from the group consisting ofbenzoyl, methoxyacetyl, tert-butylacetyl, 2,4-difluorobenzoyl,2,4-dimethylbenzoyl, 2-ethylhexanoyl, 2-propylpentanoyl,3-indolepropionyl, N-phenylanthranilyl, trans-2-carboxycyclohexanoyl,cyclohex-3-en-oyl, trans-pent-2-en-oyl, 1-methyl-1-cyclohexanoyl,1-acetylpiperidine-4-carbonyl, cyclopropanecarbonyl,methanesulfonylacetyl, 5-hexynoyl, 3-furoyl, 3,4-difluorophenylacetyl,3-benzoyl-benzoyl, 2-(trifluoromethyl)phenylacetyl,4-(trifluoromethyl)phenylacetyl,2-acetylamino-3-(1H-indol-3-yl)-propionyl, 3-(phenylsulfonyl)propionyl,2-benzyloxyphenylacetyl, benzo(b)thiophene-3-acetyl,3-fluoro-2-methyl-benzoyl, 1-methylcyclopropane-1-carboxyl,(−)-menthoxyacetyl, cyclohexyl-1-acetic acid-1-methylcarbonyl,2-(3-trifluoromethyl-phenylamino)-benzoyl, 2-ketobutyryl,2-ethyl-2-hydroxybutyryl, 5-chlorovaleryl,1-acetyl-pyrrolidine-2-carbonyl, 5-chlorothiophene-2-carboxylyl,2-(2-methoxyethoxy)acetyl, 2-methyl-3-furoyl, 6-heptynoyl,5-methylisoxazole-4-carbonyl; or X is sulfonyl and the combination ofX—R₈ is selected from the group consisting of 2-mesitylenesulfonyl,2-naphthenesulfonyl, 2-thiophenesulfonyl, 4-chlorobenzenesulfonyl,4-fluorobenzenesulfonyl, N-acetylsulfanilyl,2-acetomide-4-methyl-5-thiazolesulfonyl, 4-tert-butylbenzenesulfonyl,8-quinolinesulfonyl, 3-chloro-4-fluorobenzenesulphonyl,4-ethylbenzenesulfonyl, pentamethylbenzenesulfonyl,2,4-dichlorobenzenesulphonyl, 2-chloro-6-methylbenzenesulphonyl,3,4-difluorobenzenesulphonyl, 3,5-dichlorobenzenesulfonyl,3-chlorobenzenesulfonyl, 3-fluorobenzenesulphonyl,4-trifluoromethylbenzenesulphonyl,2-(methoxycarbonyl)thiophene-3-sulfonyl, 1-methylimidazole-4-sulfonyl,3-chloro-4-methylbenzenesulfonyl, 4-isopropylbenzenesulphonyl,3,4-dichlorobenzenesulfonyl, 1-naphthalenesulfonyl,3-nitrobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-nitrobenzenesulfonyl,2,3,5,6-tetramethylbenzenesulfonyl, p-xylene-2-sulfonyl,4-n-propylbenzenesulfonyl, 4-n-amylbenzenesulfonyl,2-chlorobenzenesulfonyl, 5-chlorothiophene-2-sulfonyl,m-toluenesulfonyl, 2-bromobenzenesulfonyl, p-styrenesulfonyl,4-pentylbenzene-1-sulfonyl, 4-n-butylbenzenesulfonyl and2-methylsulfonylbenzenesulfonyl.
 18. The compound of claim 17, wherein:Z is the structure A, wherein: m is 0; R₅ is selected from the groupconsisting of 1,4-butylene, 1,2-ethylene and 1,3-propylene; R₆ and R₇are directly attached and, combined, is 1,2-ethylene; or R₆ and R₇ arenot directly attached and are each selected from the group consisting ofhydrogen and ethyl.
 19. The compound of claim 17, wherein: Z isstructure A, wherein: m is 1; n is 3; R₅ is 1,2-ethylene; and R₆ and R₇are directly attached and, combined, is 1,2-ethylene.
 20. The compoundof claim 17, wherein: Z is structure C, wherein: K is absent or, ifpresent, is 1,3-propylene.
 21. The compound of claim 16, wherein Z isstructure B.
 22. The compound of claim 21, wherein the cyclic portion ofstructure B is selected from the group consisting of pyrrolidine,piperidine and piperazine.
 23. The compound of claim 22, wherein: thecyclic portion of structure B is selected from the group consisting of1,2-pyrrolidene, 1,2-piperidene and 1,4-piperazene, wherein R₅ isdirectly connected at the 2-position, 2-position and 4-position,respectively; R₅ is selected from the group consisting of methylene andethylene; and R₈ and R₉ are, independently selected from the groupconsisting of hydrogen, methyl, ethyl, hydroxyethyl, benzyl, cyclohexyl,isobutyl, propyl, butyl, sec-butyl, hexyl, heptyl, allyl, cyanoethyl,2-picolyl, cyclohexylmethyl, cyclohexylethane-1,1-diyl,N,N-diethylaminoethyl, N,N-dimethylaminopropyl and neopentyl; or R₈ andR₉, together with the adjoining nitrogen atom depicted in structure Bare, collectively, selected from the group consisting ofpyrrolidin-1-yl, piperidin-1-yl, 3-(carboxamide)piperidin-1-yl,2-(carboxamide)pyrrolidin-1-yl, 4-(methyl)piperazin-1-yl,morpholin-4-yl, 2-(hydroxymethyl)piperidin-1-yl,4-(ethylcarboxylate)piperidin-1-yl, 4-(phenyl)piperazin-1-yl,4-(2-pyrimidyl)-piperazin-1-yl, thiomorpholin-4-yl,4-(benzyl)piperazin-1-yl, 3-(ethylcarboxylate)piperidin-1-yl,4-(hydroxy)piperidin-1-yl, 3,5-(dimethyl)piperazin-1-yl,homopiperazin-1-yl, 4-(methyl)homopiperazin-1-yl,2-(methyl)piperidin-1-yl, 3,5-(dimethyl)piperidin-1-yl,3-(N,N-dimethylamino)pyrrolidin-1-yl, 3-(amino)pyrrolidin-1-yl,homopiperidin-1-yl, decahydroquinolin-1-yl andtertrahydroisoquinolin-1-yl.
 24. A combinatorial library of two or morecompounds of the structure:

wherein R₁ and R₄ and one of R₂ and R₃, are independently selected fromthe group consisting of a hydrogen atom, halo, hydroxy, protectedhydroxy, cyano, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl,C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂substituted alkynyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy, C₁to C₁₂ acyloxy, C₁ to C₁₂ acyl, C₃ to C₇ cycloalkyl, C₃ to C₇substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substitutedcycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C₇ toC₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, phenyl,substituted phenyl, naphthyl, substituted naphthyl, cyclic C₂ to C₇alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇heteroalkylene, substituted cyclic C₂ to C₇ heteroalkylene, carboxy,protected carboxy, hydroxymethyl, protected hydroxymethyl, protectedamino, protected (monosubstituted)amino, (disubstituted)amino, C₁ to C₁₀alkyl protected amino, C₁ to C₁₀ alkyl protected (monosubstituted)amino,C₁ to C₁₀ alkyl(disubstituted)amino, C₁ to C₁₀ substituted alkylamino,C₁ to C₁₀ substituted alkyl protected (monosubstituted)amino, C₁ to C₁₀substituted alkyl(disubstituted)amino, carboxamide, C₁ to C₁₀ alkylthio,C₁ to C₁₀ substituted alkylthio, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀substituted alkylsulfonyl, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀substituted alkylsulfoxide, phenylthio, substituted phenylthio,phenylsulfoxide, substituted phenylsulfoxide, phenylsulfonyl,substituted phenylsulfonyl and the group consisting of (i) the formula—C(O)NR¹¹R¹², (ii) the formula —SR¹¹, (iii) the formula —OR¹¹ and (iv)the formula —C(O)OR¹¹, wherein R¹¹ and R¹² are, independently, selectedfrom the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, heteroaryl,substituted heteroaryl, heterocycle and substituted heterocycle; theother of R₂ and R₃ is selected from the group consisting of a hydrogenatom, halo, hydroxy, protected hydroxy, carboxy, thio, C₁ to C₁₂ alkyl,C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ toC₁₂ substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₁ to C₁₂alkoxy, C₁ to C₁₂ substituted alkoxy, C₁ to C₁₂ acyloxy, C₁ to C₁₂ acyl,C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocyclic ring,substituted heterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂substituted heterocycloalkyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, carboxy, protected carboxy, hydroxymethyl, protectedhydroxymethyl, protected amino, protected (monosubstituted)amino,(disubstituted)amino, C₁ to C₁₀ alkyl protected amino, C₁ to C₁₀ alkylprotected (monosubstituted)amino, C₁ to C₁₀ alkyl(disubstituted)amino,C₁ to C₁₀ substituted alkyl protected amino, C₁ to C₁₀ substituted alkylprotected (monosubstituted)amino, C₁ to C₁₀ substitutedalkyl(disubstituted)amino, carboxamide, C₁ to C₁₀ alkylthio, C₁ to C₁₀substituted alkylthio, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substitutedalkylsulfonyl, C₁ to C₁₀ alkylsulfoxide, C₁ to C₁₀ substitutedalkylsulfoxide, phenylthio, substituted phenylthio, phenylsulfoxide,substituted phenylsulfoxide, phenylsulfonyl, substituted phenylsulfonyland the group consisting of (i) the formula —C(O)NR¹¹R¹², (ii) theformula —SR¹¹, (iii) the formula —OR¹¹, (iv) the formula —C(O)OR¹¹ and(v) the formula S(O)₂NR¹¹R¹², wherein R¹¹ and R¹² are, independently,selected from the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl,C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substitutedalkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, heteroaryl,substituted heteroaryl, heterocycle and substituted heterocycle; Z isthe structure A:

 or the structure B:

 or the structure C:

 wherein, in structure A, Q is the formula ((CH₂)_(n)NH)_(m), where m is0 or 1, n is 1 to 6 and the alkylene portion of Q is directly attachedto the depicted nitrogen atom in structure A; and the dotted linebetween R₆ and R₇ indicates that R₆ and R₇ are optionally directlyattached; wherein, in structure B, the depicted cyclic portion is anunsubstituted or substituted heterocycle that is fully saturated,contains 4 to 7 ring atoms, 1 to 2 nitrogen rings atoms and 0 to 1 otherheteroatoms selected from oxygen and sulfur; wherein, in structure C, Kis absent or present and, if present, is a C₁ to C₁₂ alkylene; R₅ isselected from the group consisting of C₁ to CO₁₀ alkylene, C₂ to C₁₀alkenylene, C₂ to C₁₀ alkynylene, C₁ to C₁₀ substituted alkylene, C₂ toC₁₀ substituted alkenylene, C₂ to C₁₀ substituted alkynylene,substituted epimino, C₁ to C₅ substituted alkylene epimino, thio, C₁ toC₁₀ alkylene thio, C₁ to C₁₀ substituted alkylene thio, sulfonyl, C₁ toC₁₀ alkylene sulfonyl, C₁ to C₁₀ substituted alkylene sulfonyl,sulfinyl, C₁ to C₁₀ alkylene sulfinyl, C₁ to C₁₀ substituted alkylenesulfinyl, oxy, C₁ to C₁₀ alkylene oxy, C₁ to C₁₀ substituted alkyleneoxy, C₁ to C₁₀ alkylene dioxy, C₁ to C₁₀ substituted alkylene dioxy, C₁to C₁₀ alkylene trioxy and C₁ to C₁₀ substituted alkylene trioxy; X isabsent or present and, if present, is selected from the group consistingof carbonyl, thiocarbonyl, thioester, sulfonyl and sulfinyl; where R₆and R₇ are not directly attached to each other, they are independentlyselected from the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl,C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ toC₁₂ substituted alkenyl, C₂ to C₁₂ substituted alkynyl, C₃ to C₇cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅to C₇ substituted cycloalkenyl, heterocyclic ring, substitutedheterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substitutedphenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂ substitutedheterocycloalkyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ to C₇alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, hydroxymethyl and protected hydroxymethyl; or where R₆and R₇ are directly attached to each other are, collectively selectedfrom the group consisting of C₁ to C₅ alkylene, C₂ to C₅ alkenylene, C₂to C₅ alkynylene, C₁ to C₅ substituted alkylene, C₂ to C₅ substitutedalkenylene, C₂ to C₁ substituted alkynylene, substituted epimino, C₁ toC₅ substituted alkylene epimino, thio, C₁ to C₅ alkylene thio, C₁ to C₅substituted alkylene thio, sulfonyl, C₁ to C₅ alkylene sulfonyl, C₁ toC₅ substituted alkylene sulfonyl, sulfinyl, C₁ to C₅ alkylene sulfinyl,C₁ to C₅ substituted alkylene sulfinyl, oxy, C₁ to C₅ alkylene oxy, C₁to C₅ substituted alkylene oxy, C₁ to C₅ alkylene dioxy, C₁ to C₅substituted alkylene dioxy, C₁ to C₅ alkylene trioxy and C₁ to C₅substituted alkylene trioxy; and X is absent or present and, if present,is selected from the group consisting of carbonyl, thiocarbonyl,thioester, sulfonyl and sulfinyl; and R₈ and, if present, R₉ areindependently selected from the group consisting of a hydrogen atom, C₁to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂ substitutedalkynyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substituted cycloalkyl, C₅ to C₇cycloalkenyl, C₅ to C₇ substituted cycloalkenyl, heterocyclic ring,substituted heterocyclic ring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂substituted heterocycloalkyl, phenyl, substituted phenyl, naphthyl,substituted naphthyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene, substituted cyclic C₂ to C₇heteroalkylene, protected hydroxymethyl, protected amino,(monosubstituted)amino, protected (monosubstituted)amino,(disubstituted)amino, C₁ to C₁₀ alkylamino, C₁ to C₁₀ alkyl protectedamino, C₁ to C₁₀ alkyl (monosubstituted)amino, C₁ to C₁₀ alkyl,protected (monosubstituted)amino, C₁ to C₁₀ alkyl(disubstituted)amino,C₁ to C₁₀ substituted alkylamino, C₁ to C₁₀ substituted alkyl protectedamino, C₁ to C₁₀ substituted alkyl (monosubstituted)amino, C₁ to C₁₀substituted alkyl protected (monosubstituted)amino, C₁ to C₁₀substituted alkyl(disubstituted)amino, carboxamide, protectedcarboxamide, and the group consisting of (i) the formula —C(O)NR¹¹R¹²,(ii) the formula —C(O)R¹¹, (iii) the formula —NR¹¹R¹², (iv) the formula—C(O)OR¹¹, wherein R¹¹ and R¹² are, independently, selected from thegroup consisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, heteroaryl,substituted heteroaryl, heterocycle, substituted heterocycle, C₁ to C₁₂acyl, C₁ to C₁₂ substituted acyl, phenylsulfonyl, substitutedphenylsulfonyl, C₁ to C₁₀ alkylsulfonyl, C₁ to C₁₀ substitutedalkylsulfonyl, C₁ to C₁₂ alkylaminocarbonyl, C₁ to C₁₂ substitutedalkylaminocarbonyl, phenylaminocarbonyl, and substitutedphenylaminocarbonyl; or R₈ and R₉, together with the adjoining nitrogendepicted in structure B are, collectively, selected from the groupconsisting of heterocycle and substituted heterocycle; provided that, ifX is carbonyl, R₈ is not alkoxy; and provided that X can only be absentwhere R₆ and R₇ are not directly attached to each other; or a salt ofsaid compound.
 25. The combinatorial library of claim 24, wherein: R₁and R₄ are independently selected from the group consisting of ahydrogen atom, halo, C₁ to C₁₂ alkyl and C₁ to C₁₂ substituted alkyl.26. The combinatorial library of claim 24, wherein: one of R₂ and R₃ isselected from the group consisting of a hydrogen atom, halo, C₁ to C₁₂alkyl and C₁ to C₁₂ substituted alkyl; and the other of R₂ and R₃ isselected from the group consisting of hydrogen atom, halo, hydroxy,carboxy, thio, carboxamide, the formula —C(O)NR¹¹R¹² and the formulaS(O)₂NR¹¹R¹², wherein R¹¹ and R¹² are, independently, selected from thegroup consisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl and C₁ to C₁₂ substituted heterocycloalkyl.
 27. Thecombinatorial library of claim 24, wherein R₆ and R₇ are not directlyattached to each other and are independently selected from the groupconsisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂ substitutedalkyl, C₃ to C₇ cycloalkyl and C₃ to C₇ substituted cycloalkyl.
 28. Thecombinatorial library of claim 24, wherein: R₈ and, if present, R₉ areindependently selected from the group consisting of a hydrogen atom, C₁to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₃ to C₇ cycloalkyl,C₃ to C₇ substituted cycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇substituted cycloalkenyl, heterocyclic ring, substituted heterocyclicring, C₇ to C₁₈ phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ toC₁₂ heterocycloalkyl, C₁ to C₁₂ substituted heterocycloalkyl, phenyl,substituted phenyl, cyclic C₂ to C₇ alkylene, substituted cyclic C₂ toC₇ alkylene, cyclic C₂ to C₇ heteroalkylene and substituted cyclic C₂ toC₇ heteroalkylene; or R₈ and R₉, together with the adjoining nitrogendepicted in structure B are, collectively, selected from the groupconsisting of heterocycle and substituted heterocycle.
 29. Thecombinatorial library of claim 24, wherein R5 is selected from the groupconsisting of C₁ to C₈ alkylene and C₁ to C₈ substituted alkylene. 30.The combinatorial library of claim 24, wherein R₆ and R₇ are directlyattached to each other and are, collectively, selected from the groupconsisting of C₁ to C₅ alkylene and C₁ to C₅ substituted alkylene. 31.The combinatorial library of claim 24, wherein X is absent.
 32. Thecombinatorial library of claim 24, wherein X is selected from the groupconsisting of carbonyl and sulfonyl.
 33. The combinatorial library ofclaim 24, wherein: R₁ and R₄, and one of R₂ and R₃, are independentlyselected from the group consisting of a hydrogen atom, halo, protectedhydroxy, cyano, C₁ to C₁₂ alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl,C₁ to C₁₂ substituted alkyl, C₂ to C₁₂ substituted alkenyl, C₂ to C₁₂substituted alkynyl, C₁ to C₁₂ alkoxy, C₁ to C₁₂ substituted alkoxy,phenyl, substituted phenyl, (disubstituted)amino, C₁ to C₁₀ alkylthioand C₁ to C₁₀ substituted alkylthio; the other of R₂ and R₃ is selectedfrom the group consisting of a hydrogen atom, halo, hydroxy, carboxy,thio, carboxamide, the formula —C(O)NR¹¹R¹² and the formulaS(O)₂NR¹¹R¹², wherein R¹¹ and R¹² are, independently, selected from thegroup consisting of a hydrogen atom, C₁ to C₁₂ alkyl, C₁ to C₁₂substituted alkyl, C₂ to C₁₂ alkenyl, C₂ to C₁₂ substituted alkenyl,phenyl, substituted phenyl, naphthyl, substituted naphthyl, C₇ to C₁₈phenylalkyl, C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂heterocycloalkyl and C₁ to C₁₂ substituted heterocycloalkyl; and whereR₆ and R₇ are not directly attached to each other, are independentlyselected from the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl,C₁ to C₁₂ substituted alkyl, C₃ to C₇ cycloalkyl and C₃ to C₇substituted cycloalkyl; R₈ and, if present, R₉ are independentlyselected from the group consisting of a hydrogen atom, C₁ to C₁₂ alkyl,C₂ to C₁₂ alkenyl, C₂ to C₁₂ alkynyl, C₁ to C₁₂ substituted alkyl, C₂ toC₁₂ substituted alkenyl, C₃ to C₇ cycloalkyl, C₃ to C₇ substitutedcycloalkyl, C₅ to C₇ cycloalkenyl, C₅ to C₇ substituted cycloalkenyl,heterocyclic ring, substituted heterocyclic ring, C₇ to C₁₈ phenylalkyl,C₇ to C₁₈ substituted phenylalkyl, C₁ to C₁₂ heterocycloalkyl, C₁ to C₁₂substituted heterocycloalkyl, phenyl, substituted phenyl, cyclic C₂ toC₇ alkylene, substituted cyclic C₂ to C₇ alkylene, cyclic C₂ to C₇heteroalkylene and substituted cyclic C₂ to C₇ heteroalkylene; or R₈ andR₉, together with the adjoining nitrogen depicted in structure B are,collectively, selected from the group consisting of heterocycle andsubstituted heterocycle; and R₅ is selected from the group consisting ofC₁ to C₈ alkylene and C₁ to C₈ substituted alkylene; where R₆ and R₇ aredirectly attached to each other, they are, collectively, selected fromthe group consisting of C₁ to C₅ alkylene and C₁ to C₅ substitutedalkylene; and X is absent or present and, if present, is selected fromthe group consisting of carbonyl and sulfonyl.
 34. The combinatoriallibrary of claim 24, wherein Z is the structure A.
 35. The combinatoriallibrary of claim 24, wherein Z is the structure B.
 36. The combinatoriallibrary of claim 34, wherein R₆ and R₇ are directly attached to eachother.
 37. The combinatorial library of claim 34, wherein R₆ and R₇ arenot directly attached to each other.
 38. The combinatorial library ofclaim 34, wherein the cyclic portion of structure A is selected from thegroup consisting of 1,4-piperazine and 1,4-homopiperazine.
 39. Thecombinatorial library of claim 24, wherein: R₁ and R₄ are each hydrogen;and one of R₂ and R₃ is hydrogen and the other is the formula—C(O)NR¹¹R¹², wherein one of R¹¹ and R¹² is hydrogen and the other isselected from the group consisting of 2-morpholin-4-yl-ethyl,3-pyrrolidin-1-yl-propyl, allyl, 3-fluorobenzyl, 2-piperidin-1-yl-ethyl,4-morpholino-3-propyl, ethyl-4-butyryl, 2-methoxyethyl, benzyl,4-methylbenzyl, N,N-diethylethylene, N,N-diethyl-1,3-propylene,3,5-dimethoxybenzyl, 4-fluorophenethyl, 4-fluorobenzyl,2-fluorophenethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-pyridin-2-yl-ethyl,propargyl, 2-pyrrolidin-1-yl-ethyl, 2-chlorobenzyl, cyclopropyl,pyridin-3-yl-methyl, 2-thiophenemethyl, 3-(methylthio)propyl,cyclohexanemethyl, 2-ethoxyethyl, cyclopentyl, cyclohexyl,3-chlorobenzyl, 4-methoxyphenethyl, 2-(4-chlorophenyl)ethyl,3-dimethylamino-1-propyl, 3,4-dimethoxybenzyl, 2-bromobenzyl,N-(3-propyl)-N-methylaniline, 2-propionic acid, 2-(3-phenyl)-propionicacid, 2-(4-methyl)-pentanoic acid, (±)-tetrahydrofuryl,3-imidazol-1-yl-propyl, 2-trifluoromethylbenzyl, cycloheptyl,2,4-dichlorophenethyl, 1-(3-propyl)-pyrrolidin-2-one,4-tert-butylcyclohexyl, 2,2,6,6-tetramethyl-piperidin-4-yl,5-diethylamino-2-pentyl, 1,3-dimethylbutyl, 2,4-dimethylbenzyl,thiophene-2-ethyl, 4-methoxyphenyl, 4-piperidino-1-carboxylic acid ethylester, 3-methoxybenzyl, N-1-ethyl-N-1-m-tolyl-2-ethyl,1-benzyl-piperidin-4-yl, 1-methyl-3-phenylpropyl, 2-fluorobenzyl,3-(trifluoromethyl)benzyl, piperonyl, 1-naphthalenemethyl,3,4-dichlorobenzyl, (R)-(−)-1-cyclohexylethyl,(+/−)-1-(1-naphthyl)ethyl, 4-(trifluoromethoxy)benzyl and5-guanidinopentanoic acid-2-yl.
 40. The combinatorial library of claim39, wherein Z is the structure A or the structure C, wherein: X iscarbonyl and the combination of X—R₈ is selected from the groupconsisting of benzoyl, methoxyacetyl, tert-butylacetyl,2,4-difluorobenzoyl, 2,4-dimethylbenzoyl, 2-ethylhexanoyl,2-propylpentanoyl, 3-indolepropionyl, N-phenylanthranilyl,trans-2-carboxycyclohexanoyl, cyclohex-3-en-oyl, trans-pent-2-en-oyl,1-methyl-1-cyclohexanoyl, 1-acetylpiperidine-4-carbonyl,cyclopropanecarbonyl, methanesulfonylacetyl, 5-hexynoyl, 3-furoyl,3,4-difluorophenylacetyl, 3-benzoyl-benzoyl,2-(trifluoromethyl)phenylacetyl, 4-(trifluoromethyl)phenylacetyl,2-acetylamino-3-(1H-indol-3-yl)-propionyl, 3-(phenylsulfonyl)propionyl,2-benzyloxyphenylacetyl, benzo(b)thiophene-3-acetyl,3-fluoro-2-methyl-benzoyl, 1-methylcyclopropane-1-carboxyl,(−)-menthoxyacetyl, cyclohexyl-1-acetic acid-1-methylcarbonyl,2-(3-trifluoromethyl-phenylamino)-benzoyl, 2-ketobutyryl,2-ethyl-2-hydroxybutyryl, 5-chlorovaleryl,1-acetyl-pyrrolidine-2-carbonyl, 5-chlorothiophene-2-carboxylyl,2-(2-methoxyethoxy)acetyl, 2-methyl-3-furoyl, 6-heptynoyl,5-methylisoxazole-4-carbonyl; or X is sulfonyl and the combination ofX—R₈ is selected from the group consisting of 2-mesitylenesulfonyl,2-naphthenesulfonyl, 2-thiophenesulfonyl, 4-chlorobenzenesulfonyl,4-fluorobenzenesulfonyl, N-acetylsulfanilyl,2-acetomide-4-methyl-5-thiazolesulfonyl, 4-tert-butylbenzenesulfonyl,8-quinolinesulfonyl, 3-chloro-4-fluorobenzenesulphonyl,4-ethylbenzenesulfonyl, pentamethylbenzenesulfonyl,2,4-dichlorobenzenesulphonyl, 2-chloro-6-methylbenzenesulphonyl,3,4-difluorobenzenesulphonyl, 3,5-dichlorobenzenesulfonyl,3-chlorobenzenesulfonyl, 3-fluorobenzenesulphonyl,4-trifluoromethylbenzenesulphonyl,2-(methoxycarbonyl)thiophene-3-sulfonyl, 1-methylimidazole-4-sulfonyl,3-chloro-4-methylbenzenesulfonyl, 4-isopropylbenzenesulphonyl,3,4-dichlorobenzenesulfonyl, 1-naphthalenesulfonyl,3-nitrobenzenesulfonyl, 4-bromobenzenesulfonyl, 4-nitrobenzenesulfonyl,2, 3,5,6-tetramethylbenzenesulfonyl, p-xylene-2-sulfonyl,4-n-propylbenzenesulfonyl, 4-n-amylbenzenesulfonyl,2-chlorobenzenesulfonyl, 5-chlorothiophene-2-sulfonyl,m-toluenesulfonyl, 2-bromobenzenesulfonyl, p-styrenesulfonyl,4-pentylbenzene-1-sulfonyl, 4-n-butylbenzenesulfonyl and2-methylsulfonylbenzenesulfonyl.
 41. The combinatorial library of claim40, wherein: Z is the structure A, wherein: m is 0; R₅ is selected fromthe group consisting of 1,4-butylene, 1,2-ethylene and 1,3-propylene; R₆and R₇ are directly attached and, combined, is 1,2-ethylene; or R₆ andR₇ are not directly attached and are each selected from the groupconsisting of hydrogen and ethyl.
 42. The combinatorial library of claim40, wherein: Z is the structure A, wherein: m is 1; n is 3; R₅ is1,2-ethylene; and R₆ and R₇ are directly attached and, combined, is1,2-ethylene.
 43. The combinatorial library of claim 40, wherein: Z isstructure C, wherein: K is absent or, if present, is 1,3-propylene. 44.The combinatorial library of claim 39, wherein Z is structure B.
 45. Thecombinatorial library of claim 44, wherein the cyclic portion ofstructure B is selected from the group consisting of pyrrolidine,piperidine and piperazine.
 46. The combinatorial library of claim 45,wherein: the cyclic portion of structure B is selected from the groupconsisting of 1,2-pyrrolidene, 1,2-piperidene and 1,4-piperazene,wherein R₅ is directly connected at the 2-position, 2-position and4-position, respectively; R₅ is selected from the group consisting ofmethylene and ethylene; and R₈ and R₉ are, independently selected fromthe group consisting of hydrogen, methyl, ethyl, hydroxyethyl, benzyl,cyclohexyl, isobutyl, propyl, butyl, sec-butyl, hexyl, heptyl, allyl,cyanoethyl, 2-picolyl, cyclohexylmethyl, cyclohexylethane-1,1-diyl,N,N-diethylaminoethyl, N,N-dimethylaminopropyl and neopentyl; or R₈ andR₉, together with the adjoining nitrogen atom depicted in structure Bare, collectively, selected from the group consisting ofpyrrolidin-1-yl, piperidin-1-yl, 3-(carboxamide)piperidin-1-yl,2-(carboxamide)pyrrolidin-1-yl, 4-(methyl)piperazin-1-yl,morpholin-4-yl, 2-(hydroxymethyl)piperidin-1-yl,4-(ethylcarboxylate)piperidin-1-yl, 4-(phenyl)piperazin-1-yl,4-(2-pyrimidyl)-piperazin-1-yl, thiomorpholin-4-yl,4-(benzyl)piperazin-1-yl, 3-(ethylcarboxylate)piperidin-1-yl,4-(hydroxy)piperidin-1-yl, 3,5-(dimethyl)piperazin-1-yl,homopiperazin-1-yl, 4-(methyl)homopiperazin-1-yl,2-(methyl)piperidin-1-yl, 3,5-(dimethyl)piperidin-1-yl,3-(N,N-dimethylamino)pyrrolidin-1-yl, 3-(amino)pyrrolidin-1-yl,homopiperidin-1-yl, decahydroquinolin-1-yl andtertrahydroisoquinolin-1-yl.
 47. A method of making the compound ofclaim 1, comprising displacing a leaving group on the 2-position of abenzoxazole derivative with a diamine derivative selected from the groupconsisting of formula A:

formula B:

 and formula C:

 wherein, in formula A, Q is the formula ((CH₂)_(n)NH)_(m), where m is 0or 1, n is 1 to 6 and the alkylene portion of Q is directly attached tothe depicted nitrogen atom in formula A; and the dotted line between R₆and R₇, which are variable groups, indicates that R₆ and R₇ areoptionally directly attached; wherein, in formula B, the depicted cyclicportion is an unsubstituted or substituted heterocycle that is fullysaturated, contains 4 to 7 ring atoms, 1 to 2 nitrogen rings atoms and 0to 1 other heteroatoms selected from oxygen and sulfur, and R₅, R₈ andR₉ are variable groups; wherein, in formula C, K is absent or presentand, if present, is a C₁ to C₁₂ alkylene, X optionally present as acarbonyl, thiocarbonyl, thioester, sulfonyl or sulfinyl group, and R₈ isa variable group.
 48. The method of claim 47, wherein —Q—X—R₈ of formulaA or —X—R₈ of formula C is attached to the rest of the formula byreplacing a hydrogen.
 49. The method of claim 47, wherein —NR₈R₉ offormula B is attached to the rest of the formula by displacing a leavinggroup.
 50. The method of claim 47, wherein said benzoxazole derivativeis attached to resin.